19→nor→steroids

ABSTRACT

Novel 19-nor-steroids of the formula ##STR1## wherein the A and B rings have a structure selected from the group consisting of ##STR2## having hormonal properties and their preparation and intermediates.

STATE OF THE ART

Related prior art are U.S. Pat. No. 4,477,445; No. 4,540,686 and No. 3,922,292 and French Patent No. 2,582,654.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds of formula I and a novel process and novel intermediates for their preparation.

It is another object of the invention to provide novel hormonal compositions and novel methods of inducing hormonal reactions in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are 19-nor-steroids of the formula ##STR3## wherein the A and B rings have a structure selected from the group consisting of ##STR4## are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, R₃ is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and acyl of an organic carboxylic acid of 1 to 7 carbon atoms, R₁₇ and R₁₇ ' together form ═0 or R₁₇ is --OH or acyloxy and R₁₇ ' is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms, all optionally substituted, X is selected from the group consisting of --CH₂ --, --CH₂ O--, arylene and arylenoxy linked to the C ring through a carbon atom, Y is selected from the group consisting of a simple bond and saturated and unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of arylene, --O-- and optionally oxidized --S-- and optionally terminated with aryl, Z is a simple bond or --CH₂ O-- linked to Y by a carbon atom, R_(A) and R_(A) ' being individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of aryl, alkylamino, dialkylamino, --OH, halogen and esterified carboxyl or R_(A) and R_(A) ' taken together with nitrogen to which they are attached form a 5 to 6 ring heterocycle optionally containing at least one heteroatom selected from the group consisting of --S--, --O-- and --N-- optionally substituted with alkyl of 1 to 4 carbon atoms with the proviso 1) that both of R_(A) and R_(A) ' are not hydrogen and 2) when Z and Y are both simple bonds, X is not --CH₂ -- or --CH₂ O--.

Examples of R₃, R₂ and/or R₂ ' as alkyl are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl and isobutyl, preferably methyl. Examples of R₃ as acyl are acetyl, propionyl, butyryl and benzoyl.

When R₁₇ is an acyloxy, it is a derivative of an aliphatic or cycloaliphatic carboxylic acid, saturated or unsaturated and especially alkanoic acids such as for example, acetic acid, propionic acid, butyric acid or isobutyric acid, valeric acid or undecylic acid, a hydroxyalkanoic acid such as hydroxyacetic acid; cycloalkylcarboxylic acids or cycloalkylalkanoic acids such as cyclopropylcarboxylic acid, cyclopentylcarboxylic acid or cyclohexyl carboxylic acid, cyclopentyl or cyclohexyl acetic acid or propionic acid, benzoic acid, salicylic acid or a phenylalkanoic acid such as phenylacetic acid or phenylpropionic acid, an amino acid such as diethylaminoacetic acid or aspartic acid or formic acid. It is preferably a derivative of acetic acid, propionic acid or butyric acid.

When R₁₇ ' is alkyl, it is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl and most preferably, methyl.

When R₁₇ ' is alkenyl, it is preferably vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl and most preferably vinyl or propenyl. When R₁₇ ' is alkynyl, it is preferably ethynyl, propynyl, propargyl, butynyl or isobutynyl and most preferably ethynyl or propynyl.

The expression optionally substituted applied to the alkyl, alkenyl or alkynyl includes at least one member of the group consisting of halogen, such as fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino or methyl ethylamino, each of the dialkylaminos being optionally in the oxidized form; aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylaminomethyl or ethyl, dialkylaminoalkoxy such as dimethylaminoethoxy, optionally acylated hydroxyl, for example acetoxy or ##STR5## in which n=2 to 5, such as acetyl, propionyl, butyryl, benzoyl, free or esterified carboxy and alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano, trifluoromethyl, aryl such as phenyl, furyl, thienyl or aralkyl such as benzyl, these being optionally substituted by alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or by alkoxy, alkylthio, alkylamino or di-alkylamino indicated above.

When X is arylene, it is preferably phenylene and when X is arylenoxy, it is preferably phenylenoxy.

When Y is saturated or unsaturated linear or branched aliphatic chain, it can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, or tert-butylene, n-pentylene, n-hexylene, 2-methyl pentylene, 2,3-dimethyl butylene, n-heptylene, 2-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethyl pentylene, 3-ethylpentylene, n-octylene, 2,2-dimethylhexylene, 3,3-dimethylhexylene, 3-methyl 3-ethylpentylene, nonylene, 2,4-dimethyl heptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-penta-decylene, n-hexadecylene n-heptadecylene or n-octadecylene, preferably n-nonylene or n-decylene. Equally it can be one of the following, vinylene, isopropylene, allylene, 2-methylallylene or isobutenylene, and when the chain is interrupted or terminated by one or more arylenes, it is preferably phenylene, it being understood that terminated relates to anyone of the two extremities of Y.

When RA or RA' is alkyl, it can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimetyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyle, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl.

The aforementined radicals can be substituted by one or more aryl such as phenyl, furyl, thienyl, preferably phenyl; by one of or more alkylamino or dialkylamino such as dimethylamino or by one or more esterified carboxyl such as by methoxycarbonyl or an ethoxycarbonyl, by one or more halogen atoms for example, fluorine, chlorine or bromine. 2,2,3,3,4,4,4-heptafluorobutyl or 2-chloro-2-methylpropyl can notably be cited.

When RA and RA' form with the nitrogen atom to which they are linked a heterocycle with 5 to 6 links, it is a saturated heterocycle, preferably pyrrolidine or piperidine optionally substituted by alkyl such as methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl or an unsaturated heterocycle, preferably pyrrole or pyridine optionally substituted by alkyl such as methyl, optionally containing another heteroatom, preferably morpholine, piperazine or pyrimidine, optionally substituted by alkyl, preferably methyl or ethyl.

The preferred compounds of formula I of the invention are those wherein the A and B rings are ##STR6## and those wherein A and B are ##STR7## in which R₂ " or R₂ "' are hydrogen or methyl, preferably hydrogen, those in which Z is a simple bond and those in which R₁₇ is hydroxyl, those in which R₁₇ ' is hydrogen, ethynyl or propynyl, those in which X is methylene and Y is saturated linear chain of 5 to 10 carbon atoms optionally interrupted by an oxygen atom and those in which X is phenylene and Y is a saturated linear chain of 3 to 10 carbon atoms optionally interrupted by an oxygen atom and those in which X is phenylenoxy and Y is saturated linear chain of 3 to 10 carbon atoms optionally substituted by an oxygen or sulfur atom.

Among the preferred compounds of the invention are those in which either RA and RA' are both methyl or RA is hydrogen or methyl and RA' is butyl, or RA is methyl and RA' is isopropyl, dimethylaminoethyl, benzyl or heptafluorobutyl or RA and RA' form together a piperazine optionally N-substituted or a pyrrolidine.

Among the specific preferred compounds of the invention are 11β-N-(2-dimethylaminoethyl)-17β-hydroxy-N-methyl-3-oxo-Δ.sup.4,9 -estradien-undecanamide, N-butyl-4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-N-methyl-benzene octanamide, 3,17β-dihydroxy-N-methyl-N-isopropyl-11β-Δ¹,3,5(10) -estratrien-undecanamide, N-butyl-3,17β-dihydroxy-N-methyl-19-nor-11β-(17α-Δ.sup.1,3,5(10) -pregnatrien-20-yn)-undecanamide, 3,17β-dihydroxy-N-methyl-N-isopropyl-19-nor-11β-17α-.DELTA.¹,3,5(10) -pregnatrien-20-yn)-undecanamide, [[8-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-octyl]-oxy]-N-methyl-N-isopropyl-acetamide, N-butyl-8-[4-(3,17β-dihydroxy Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy-N-methyl octanamide, N-butyl-[5-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-pentoxy]-N-methyl acetamide, 2-[(7-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl]-6-heptyl]-oxy]-N-butyl-N-methyl acetamide, 3,17β-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-Δ¹,3,5(10) -estratrien-11β-yl undecanamide and 8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl]-N-butyl-N-methyl octynamide.

The novel process of the invention for the preparation of the compounds of formula I comprises reacting a compound of the formula ##STR8## wherein X, Y, R₁₇ and R₁₇ ' have the above definitions with R₁₇ being other than --OH either with an oxidizing agent to obtain a product of the formula ##STR9## reacting the latter with an agent permitting the activation of the carboxylic function, then with a compound of the formula ##STR10## wherein RA and RA' have the above definitions to obtain the product of formula Ia corresponding to the compound of formula I in which Z is a simple bond and the rings A and B are ##STR11## wherein R₂ and R₂ ' are hydrogen or with a compound capable of introducing ##STR12## to obtain a compound of formula I'a which is a compound of formula I wherein Z is --CH₂ O-- and A and B rings have the definition of formula I_(a), the compounds of formulae I_(a) or I_(a) ' optionally being reacted with a reducing agent when R₁₇ and R₁₇ ' together form ═O, then if appropriate, reacting the 17-hydroxylated compound with an acylation agent, or with a saponification agent when R₁₇ is an acyloxy, to obtain a product of formula Ia or I_(a) ' in which R₁₇ has the above meaning, then if desired, reacting one of the products of formula Ia or I_(a) ', either to obtain an alkylation at position 2, when at least one of R₂ and R₂ ' is hydrogen, or reacts with an aromatization agent of ring A, then to a saponification agent to obtain the products of formula Ib corresponding to products of formula Ia and the products of formula I_(b) ' corresponding to the products of formula I.sub. a ' in which the rings A and B are ##STR13## optionally reacting the products of formula Ib and Ib' to an alkylation or acylation reaction of the 3-hydroxy, then, if desired, either, when R₁₇ and R₁₇ ' together form ═0 to a reducing agent or to a metallic complex of the formula

    M-R.sub.17 '                                               V

wherein M is a metallic ion and R₁₇ ' has the above definition other than hydrogen, or when R₁₇ is a hydroxy reacting with an acylation agent selective at position 17, then, if desired, with one of the products of formula I obtained above, or when RA or RA' is hydrogen with an appropriate alkylation agent.

The compounds of formula I are 19-nor steroids having: either a chain at the 11β-position containing a substituted amide function which compounds are then chosen from among the compounds of formulae Ia and Ib, or a chain at the 11β-position containing a substituted carbamate function which compounds are chosen from among the compounds of formulae Ia' and Ib'.

The compounds of formula I_(a) ' are obtained by reacting a compound of formula II either with an activator of the hydroxyl such as phosgene, then with a primary or secondary amine of formula IV in a neutral solvent such as methylene chloride or tetrahydrofuran in the presence of a base such as potassium carbonate or methylamine, or with an isocyanate of the formula RA-N═C═O to obtain a product in which RA' is hydrogen.

The compounds of formula Ia are obtained by reacting a compound of formula III activated, for example in the form of the mixed anhydride with an agent such as chloroformate, for example, isobutyl chloroformate, in the presence of a base such as a tertiary amine like N-methylmorpholine in an annydrous solvent such as a chlorinated solvent, i.e., methylene chloride with the amine of formula IV.

The product of formula III is obtained by using an oxidizing agent such as, for example, the mixture CrO₃ -sulfuric acid in a neutral solvent such as acetone.

In a preferred embodiment of the invention:

The compounds of formula II contain a 11β chain terminated by an alcohol function selected from the following Table:

    ______________________________________                                         X           Y                 CH.sub.2 OH                                      ______________________________________                                          ##STR14##  (CH.sub.2).sub.7  CH.sub.2 OH                                      "           CC(CH.sub.2).sub.5                                                                               CH.sub.2 OH                                      "           CC(CH.sub.2).sub.5OCH.sub.2                                                                      CH.sub.2 OH                                       ##STR15##  (CH.sub.2).sub.5OCH.sub.2                                                                        CH.sub.2 OH                                      "           (CH.sub.2).sub.7  CH.sub.2 OH                                      CH.sub.2    (CH.sub.2).sub.9  CH.sub.2 OH                                      "           (CH.sub.2).sub.7 OCH.sub.2                                                                       CH.sub.2 OH                                      ______________________________________                                    

as illustrated in the examples hereafter.

The compounds of formula III contain a 11β-chain terminated by a carboxylic acid corresponding to the oxidation product of a chain chosen from among the 11β-chains terminated by one of the alcohol functions cited above.

The compound of formula IV is chosen from the following amines: butylamine, methylbutylamine, dimethylamine, methylisopropylamine, methyldimethylaminoethylamine, methylbenzylamine, pyrrolidine or N-methylpiperazine which are known products.

When the compound of formulae Ia or I_(a) ' has a 17β-ketone, the corresponding 17β-hydroxyl steroid is obtained by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol or triterbutoxylithium aluminium hydride in tetrahydrofuran.

When the compound of formulae Ia or I_(a) ' has a 17β-hydroxy, the corresponding 17-acyloxylated steroid is obtained by the action of an acylation agent, for example an acetylation agent such as acetic anhydride in pyridine, optionally in the presence of 4-dimethylamino-pyridine.

When the compounds of formulae Ia or I_(a) ' have 17β-acyloxy, the corresponding 17β-ol steroid is obtained with a saponification agent such as potassium hydroxide in an alcoholic medium.

When the compounds of formulae Ia or I_(a) ' has one or two hydrogen atoms at position 2 or/and 2', the corresponding mono or dialkylated steroid at position 2 and 2' is obtained by the action of an alkylation agent, preferably a methylation agent such as methyl iodide.

The compounds of formulae Ib and I_(b) ' which are steroid derivatives of estradiol having a 11β-chain containing a substituted amide function or a substituted carbamate function are obtained starting with the compounds of formulae Ia and I_(a) ' respectively, by the action of an aromatization agent such as palladium hydroxide on magnesia in methanol or a mixture of acetyl bromide and acetic anhydride at a temperature not exceeding that of ambient followed by a saponification reaction using, for example, potassium hydroxide in methanol, sodium bicarbonate or methanol in the presence of hydrochloric acid.

When the compounds of formulae Ib or I_(b) ' have a 3-hydroxy, the corresponding alkylated steroids is obtained with an alkylation reagent such as alkyl iodide or an alkyl sulfate, for example, methyl sulfate or the corresponding acylated steroid by the action, of a standard acylation reagent such as an acyl halide like acetyl chloride.

When the compounds of formula Ib or I_(b) ' have a 17 ketone, the corresponding 17β-hydroxyl steroids are obtained under the conditions described above for Ia or I_(a) ', for example by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol and the corresponding compound of formulae Ib or I_(b) ' wherein R₁₇ ' is alkyl, alkenyl or alkynyl optionally substituted are obtained by using as a complex, for example, a lithium complex according to the process of EP Patent Application 57,115.

When the compounds of formula Ib or I_(b) ' have a 17β-hydroxy, the acyloxyl steroids can be obtained by the action of a selective acylation agent such as acetic anhydride in pyridine.

When RA or RA' is hydrogen, the corresponding alkylated product may be obtained by the action of an alkyl halide, for example methyl or ethyl iodide, methyl or ethyl bromide in a solvent such as tetrahydrofuran. It is well understood that if R₁₇ ' contains an alkyl, alkenyl or alkynyl substituted by a reactive function, this can be provisionally protected by the usual methods.

The novel process of the invention for the preparation of compounds of formula I' wherein X is arylene and Y is aliphatic optionally linked to arylene by a double or triple bond and having at least 3 carbon atoms or linked to arylene through an oxygen atom comprises reacting a compound of the formula ##STR16## wherein W is either --OH or --C.tbd.CH, the rings A' and B', Ra₁₇ and Ra₁₇ ' having the same meanings as indicated above for rings A and B, R₁₇ and R₁₇ ' and in which the 3- and 17-reactive functions are optionally protected or, when W is --C.tbd.CH reacted with a halogenation agent of the formula ##STR17## wherein Hal is halogen, Z, RA, and RA' have the above definitions and Y' is aliphatic Y having 2 carbon atoms missing, in the presence of a strong base, and optionally to the action of a deprotection agent to obtain a product of the formula ##STR18## which optionally is reacted with a partial or total reducing agent of the triple bond to obtain a product of the formula ##STR19## or, in the case where W is -OH to the action of a halogenated derivative of the formula ##STR20## in which Hal, Y, Z, RA and RA' have the above definitions in the presence of an alkaline agent, and optionally reacting with a deprotection agent to obtain a product of the formula ##STR21## which optionally, when Y is an unsaturated aliphatic is reacted with a partial or total reducing agent, and the products of formula I_(A) ', I_(B) ' or I_(A) " may be subjected to any one of the reactions indicated above for Ia, Ia', Ib and Ib'

In a preferred process of the invention, the optional protection groups of the 3- or 17-hydroxyl are selected from the standard groups such as tetrahydropyranyl and tert.-butyl and the halogen of Hal may be bromine, chlorine or idodine. The strong base used is, for example, butyllithium or sodium hydride and the alkaline agent used is an alkali metal hydroxide such as sodium hydroxide. The deblocking of the protected functions may be effected using of a standard hydrolysis agent such as hydrochloric acid and the optional reduction of the triple bond is effected either using hydrogen in the presence of palladium on activated charcoal, barium sulfate and optionally a base such as pyridine or quinoline in the case of a partial reduction. Palladium hydroxide is used alone in the case of a total reduction. In the compounds of formula X used initially, W is in the para position.

In a variation of the processes, the products of formula I wherein Z is a simple bond and Y is a linear aliphatic terminated by vinylene before the amide function, a compound of the formula ##STR22## corresponding to the product of formula II in which Y" is the aliphatic chain Y containing 2 carbon atoms missing, is reacted with an oxidation agent to obtain the corresponding aldehyde which is reacted with a phosphorane of the formula ##STR23##

The products of formula I in which Y is a branched aliphatic chain can be prepared by alkylation of the products of formula I in which Y is a linear aliphatic chain after having, if appropriate, blocked the 3- and/or 17- reactive functions. The alkylation is effected by using an alkyl halide such as methyl iodide in the presence of lithium diisopropylamide. The products of formula III can be prepared by alkaline hydrolysis of the corresponding products containing at 11β position a a --X--Y--CN chain products obtained starting with products of formula II' as defined above in which one protects the hydroxyl functions, then is reacted with a halogenation agent such as an alkali metal halide, for example, sodium iodide and then an alkali metal cyanide such as potassium cyanide.

The novel hormonal compositions of the invention are comprised of an hormonally effective amount of at least one compound of formula I and an inert pharmaceutical carrier or excipient. The compositions may be in the form of tablets, dragees, capsules, granules, suppositories, pessaries, ointment, creams, gels, microspheres, implants, patches and injectable solutions or suspensions.

Examples of suitable excipients are talc, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants and emulsifiers and preservatives.

The compositions containing compounds of formula I present interesting pharmacological properties. The study of products on the hormonal receptors has brought to the fore that the compounds of formulae Ia and Ia' possess glucocoticoid or antiglucocorticoid, progrestomimetic or antiprogestomimetic, androgen or antiandrogen, antimineralocorticoid, estrogen or anti-estrogen activity and the compounds of formulae Ib and I'b possess particularly a remarkable anti-estrogen activity and anti-proliferative properties as shown by the results of tests given intra.

These properties make the compositions containing compounds of formula Ia and I'a useful for combatting the side effects of glucocorticoids and permit the combatting of disorders due to a hypersecretion of glucocorticoids and notably the combatting of aging in general and more particularly the combatting of hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as the depression of immunity and insomnia. These compositions are equally of interest in the treatment of certain hormonal-dependent tumors.

The compositions containing compounds of formulae Ia and I'a which possess antiprogestomimetic properties can be used for the preparation of original contraceptives or as abortion agents and are useful for inducing (menstrual) periods in women and more generally in warm-blooded female animals. The compositions are administered during the periods where progesterone plays an essential physiological role, i.e., during the luteal phase of the cycle, at the moment of nidation (or implanation of the embryo) and during pregnancy. One method of contraception of the invention consists of administering to the woman at least one of the products of formula Ia or Ia' over 1 to 5 days, preferably at the end of the cycle. This product is then preferably administered orally or in vagino but it can also be administered parenterally and endonasally.

The compositions containing the compounds of formulae Ia and Ia' possessing anti-progestomimetic properties are also useful against hormone irregularities and, are of interest in the treatment of hormono-dependent tumors. Their actions on hypophysial secretions make the products usable in the menopause and these compositions can be used in the synchronization of estrus in farm animals, particularly cattle and sheep and for controlling the fertility of pets such as dogs or cats. Equally the compositions containing compounds of formulae Ia and Ia' can have progestomimetic properties and can be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiencies.

The compositions of compounds of formulae Ia and Ia' which possess anti-androgenic properties can be used in the treatment of hypertrophia and cancer of the prostate, hyperandrogenia, anemia, hirsutism and acne. Equally they can be used for male contraceptives.

The compositions of compounds of formulae Ia and Ia' which possess estrogenic properties make them useful in the treatment of disorders linked to a hypofolliculinia for example amenorrhea, dysmenorrhea, repeated miscarriages, premenstrual troubles as well as in the treatment of the menopause and of osteoporosis.

The anti-estrogen and anti-proliferation properties of compositions containing the compounds of formulae Ib and Ib' make them useful in the treatment of mammary carcinomas and their metastases and in the treatment of benign tumors of the breast.

Among the preferred compositions of the invention are those containing the compounds of Examples 8, 16, 19, 21, 35, 37, 43, 46, 55, 71 and 75.

The novel method of inducing hormonal activity in warm-blooded animals, including humans, comprises administering to warm-blooded animals an hormonally effective amount of at least one compound of formula I. The compounds may be administered orally, rectally or parenterally and the usual daily dose is 0.013 to 1.33 mg/kg depending upon the method of administration, the condition being treated and the specific compound being administered.

The compounds of formulae II and III are novel intermediates and an object of the invention.

The compounds of formula II may be prepared by reacting a magnesium derivative of a halogenated alcohol of the formula

    Hal--X--Y--CH.sub.2 OR                                     VI

wherein X and Y have the above definitions, Hal is a halogen and R is hydrogen or an alcohol protecting groups such as ##STR24## in the presence of a copper salt with a compound of the formula ##STR25## wherein K is a ketone protector group such as a cyclic ketal to obtain a compound of the formula ##STR26## optionally reacting the latter with a lithium derivative of a compound of the formula

    H--R.sub.17 '                                              IX

wherein R₁₇ ' has the above definition other than hydrogen or with a reducing agent, then optionally with an acylation agent and then to a dehydration and hydrolysis agent capable of liberating the 3-keto-Δ⁴ function and the alcohol function to obtain the compound of formula II.

The products of formula VII are known products and their preparation is described, for example, in EP Patent No. 0,057,115. The products of formula X are described notably in European Patent Application No. EP 0,245,170 and specific examples of the preparation of products of formula X are described hereinafter in the examples. Examples of the preparation of products of formulae XI and XII are in the experimental part.

Among the preferred new products of formula II of the invention are 17β-acetyloxy-11β-[(8-hydroxy-octyl)phenyl]-Δ⁴,9 -estradien-3-one, 11β-(12-hydroxy-dodecyl)-Δ⁴,9 -estradiene-3,17-dione and 11β-(8-hydroxyoctyl)-Δ⁴,9 -estradien-3,17-dione.

Among the preferred products of formula III of the invention are 17β-acetyloxy-3-oxo-11β-Δ⁴,9 -estradiene-undecanoic acid, 3,17-dioxo-11β-Δ⁴,9 -estradiene undecanoic acid and 17β-hydroxy-3-oxo-17α-(1-propynyl)-11β-Δ⁴,9 -estradiene undecanoic acid.

The following products are products able to be obtained within the scope of the present invention:

    ______________________________________                                          ##STR27##                                                                     Y             Z     Re              R'.sub.17                                  ______________________________________                                         CC(CH.sub.2).sub.5                                                                           --                                                                                    ##STR28##      H                                          "             --                                                                                    ##STR29##      H                                          "             --                                                                                    ##STR30##      H                                          "             --                                                                                    ##STR31##      H                                          "             --                                                                                    ##STR32##      H                                          CCCH2-φ -OCH2                                                                            --                                                                                    ##STR33##      H                                          CCCH2O-φ -CH2                                                                            --                                                                                    ##STR34##      H                                          (CH2)7        --                                                                                    ##STR35##                                                                                      ##STR36##                                 ______________________________________                                    

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

PREPARATION 1 17β-acetyloxy-11β-[4-(2-hydroxymethyl)-phenyl]-Δ⁴,9 -estradiene-3-one Step A (5α,11β)-3-(1,2-ethanediyl cyclic acetal) of 5α-hydroxy-11β-[4-[2-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-methyl]-phenyl]-.sup.Δ9 -estrene-3,17-dione Preparation of the Magnesium Reagent

To a suspension of 1.4 g of magnesium turnings in 20 ml of tetrahydrofuran, 19.9 g of the brominated derivative obtained from preparation 9 in solution in 60 ml of tetrahydrofuran were added dropwise followed by stirring for 1 hour at 50° C. to obtain a solution with a titer=0.85 mole/liter.

Condensation

For 10 minutes at ambient temperature, a solution of 4.5 g of 3-(1,2-ethanediyl cyclic acetal) of 5α,10α-epoxy-Δ⁹,11 estrene-3,17-dione [EP 0,057,115 (Example 7)] in 45 ml of tetrahydrofuran and 0.4 g of cupric chloride was stirred and over a period of 20 minutes, 50 ml of the magnesium reagent above were added without exceeding 27° C. After 90 minutes of stirring, the mixture was poured into an ice-cooled solution of ammonium chloride. The aqueous phase was extracted once with ethyl acetate and 3 times with methylene chloride to obtain 15.423 g of a product which was chromatographed over silica (eluant: cyclohexane-ethyl acetate (7-3)) to obtain 6.29 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH at 5               3508 cm.sup.-1                                           C═O               1733 cm.sup.-1                                           Aromatic              1510 cm.sup.-1                                           O--Si probable                                                                 ______________________________________                                    

Step B 3-(1,2-ethanediyl cyclic acetal) of 5α,17β-dihydroxy-11β-[4-2-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-methyl]-phenyl]-Δ⁹ -estren-3-one

To a solution of 6.15 g of the product of Step A in 100 ml of methanol, 6 g of sodium boron hydride were added over 15 minutes and the mixture was stirred for two hours and poured into 500 ml of water and extracted with methylene chloride. The organic phase was evaporated to dryness to obtain 6.17 g of the desired product which was used as such in the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH at 17              3611 cm.sup.-1                                           OH at 5               3508 cm.sup.-1                                           Aromatic              1509 cm.sup.-1                                           O--Si probable                                                                 ______________________________________                                    

Step C 17β-acetyloxy 11β-[4-(2-methyl)-phenyl]-Δ⁴,9 -estradien-3-one a) Acetylation

To a solution of 6.1 g of the product of Step B in 52 ml of pyridine and 1.15 g of 4-dimethylamino-pyridine, 5.2 ml of acetic anhydride were added and the mixture was stirred for 20 minutes and poured into 200 ml of an ice-cooled solution of sodium bicarbonate. The mixture was stirred for 10 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness to obtain 6.828 g of the expected amorphous product.

b) Hydrolysis

The said product was taken up in 40 ml of 2N hydrochloric acid and 50 ml of ethanol and was stirred for 1 hour at ambient temperature and concentrated to half-volume under reduced pressure. The mixture was diluted with 100 ml of water, and extracted with methylene chloride. The organic phase was evaportated to dryness under reduced pressure and the residue was chromatographed over silica (eluant: cyclohexane-ethyl acetate (1-1)) to obtain 3.39 g of the desired product.

    ______________________________________                                         IR Spectrum: CHCl.sub.3 (on Nicolet)                                           ______________________________________                                         OH                 3618 cm.sup.-1                                              C═O            1728 cm.sup.-1 OAc                                          Dienone            1656                                                                           1602                                                        Aromatic           1509 cm.sup.-1                                              ______________________________________                                    

PREPARATION 2 3,17-dioxo-11β-Δ⁴,9 -estradiene-pentanoic acid Step A 3-(1,2-ethanediyl cyclic acetal) of 11β-(5-hydroxy-pentyl)-Δ⁹ -estrene-5α-o1-3,17-dione Preparation of the Magnesium Reagent of 1-Chloro-5-Pentanol

To a solution of 24.6 ml of 1-chloro-5-propanol in 246 ml of tetrahydrofuran, 300 ml of a 0.67M/liter solution of the magnesium reagent of 2-chloropropane in tetrahydrofuran was added over 20 minutes at -20° C. and the mixture was stirred for 20 minutes at -20° C. 7.3 g of the magnesium reagent in shavings were added followed by 0.5 ml of dibromoethane. The mixture was refluxed for 1 hour, 0.5 ml of dibromoethane were added and then reflux was continued for two hours. The mixture returned to ambient temperature to obtain the solution of the desired magnesium reagent titering 0.18M/liter.

Condensation

To a mixture of 12 g of the 5,10 epoxy compound of EP 0,057,115 (Example 7) and 600 mg of cuprous chloride in 150 ml of tetrahydrofuran, 570 ml of the magnesium reagent were added dropwise at -5° C. and the mixture was stirred for a further 30 minutes and poured into a mixture of 250 ml of a saturated solution of ammonium chloride and 250 g of ice. The mixture was extracted with chloroform and the organic phase was washed with a saturated solution of sodium chloride, dried and evaporated to to dryness under reduced pressure. The 35 g of the residue were chromatographed over silica (eluant: methylene chloride-acetone (85-15)) to obtain 13.5 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17 keto              1733 cm.sup.-1                                            OH primary           3623 cm.sup.-1                                            OH at 5              3567 cm.sup.-1                                            C═C              1625 cm.sup.-1                                            ______________________________________                                    

Step B 11β(5-hydroxy pentyl)-Δ⁴,9 -estradiene-3,17-dione

For 90 minutes, a mixture of 5 g of the product of Step A, 110 ml of ethanol and 28 ml of 2N hydrochloric acid was stirred and the mixture was made alkaline to pH of about 9 with concentrated ammonia. The mixture was washed with water, with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 4.8 g of residue were chromatographed over silica (eluant: methylene chloride-acetone (85-15)) to obtain 3.97 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH primary       3264 cm.sup.-1                                                Ketone at 17     1736 cm.sup.-1                                                Dienone          1656 cm.sup.-1 - 1602 cm.sup.-1                               ______________________________________                                    

Step C 3,17-dioxo-11β-Δ⁴,9 -estradiene-pentanoic acid

To a solution of 2.9 g of the product of Step B in 140 ml of acetone cooled down to -4° C., 1 ml of Heilbron-Jones reagent were added over 25 minutes at 0° to -4° C. and the mixture was stirred for a further 5 minutes at 0° C. The excess reagent was destroyed by the addition of 2.5 ml of methanol and a solution of 22 g of barium carbonate in 220 ml of water was added. The mixture was stirred for 1 hour at ambient temperature and filtered to remove the mineral salts which were washed 5 times with 200 ml of acetone. The acetone was evaporated and the aqueous phase was extracted 4 times with 200 ml of methylene chloride. The organic phase was washed with water, with sodium chloride in saturated solution and evaporated to dryness under reduced pressure to obtain 3.4 g of the desired product used as such in the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17 keto               1736 cm.sup.-1                                           C═O               1709 cm.sup.-1                                           Conjugated ketone     1657 cm.sup.-1                                           C═C               1602 cm.sup.-1                                           ______________________________________                                    

PREPARATION 3 3,17-dioxo-11β-Δ⁴,9 -estradiene-heptanoic acid Step A 3-(1,2-ethanediyl cyclic acetal) of 11β-(7-hydroxy heptyl)-Δ⁹ -estrene-5α-o1-3,17-dione

Using the procedure of Step A of Preparation 2, 14.4 g of 1-chloro-7-heptanol [obtained in Preparation 10 starting from 13.9 g of the 5α, 10α-epoxide of EP 0,057,115 Example 7] yielded. 26.9 g of crude product which was chromatographed over silica (eluant: methylene chloride-acetone-triethylamine (85-15-0.4)) to obtain 9 g of the desired product. The latter was chromatographed once more (eluant: ethyl acetate-cyclohexane-triethylamine (60-40-0.4)) to obtain 8.17 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17 keto                1733 cm.sup.-1                                          Primary alcohol        3622 cm.sup.-1                                          Tertiary alcohol OH    3508 cm.sup.-1                                          ______________________________________                                    

Step B 11β-(7-hydroxyheptyl)-Δ⁴,9 -estradiene-3,17-dione

Using the procedure of Step B of Preparation 2, 2.5 g of the product of Step A were reacted and after chromatography over silica (eluant: cyclohexane-diethyl acetate (1--1)), 1.935 g of the desired product were obtained.

    ______________________________________                                         IR Spectrum:                                                                   ______________________________________                                         CH.sub.2 OH        3626 cm.sup.-1                                              17 keto            1734 cm.sup.-1                                              Dienone            1654- 1602 cm.sup.-1                                        ______________________________________                                    

STEP C 3,17-dioxo-11β-Δ⁴,9 -estradiene heptanoic acid

Using the procedure of Step C of Preparation 2, 3.2 g of the product of Step B were reacted to obtain 3.04 g of the desired product which was used as such in the following step.

PREPARATION 4 17β-acetyloxy-11β-[4-(8-hydroxy octyl)-phenyl]-Δ⁴,9 -estradiene-3-one Step A 3-(1,2-ethanediyl cyclic acetal) of 11β-[4-[8-[[(1, 1-dimthyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-Δ⁹ -estrene-5α-o1-3,17-dione

Using the procedure of Step A of Preparation 1, 3.171 g of the epoxide of EP 0,057,115 (Example 7) and 9.9 g of dimethyl tert.-butyl silyl octanyloxy bromobenzene (of Preparation 11) were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl-acetate (6-4)), 4.127 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH type 5-OH    3510 cm.sup.-1                                                 Aromatic        1510 cm.sup.-1                                                  ##STR37##       836 cm.sup.-1                                                 17 keto         1733 cm.sup.-1                                                 ______________________________________                                    

Step B 3-(1,2-ethanediyl cyclic acetal) of 11β-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-Δ⁹ -estren-5α,17β-diol-3-one

Using the procedure of Step B of preparation 1, 2.62 g of the product of Step A were reacted to obtain 2.6 g of the desired product for use as is in the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3) on the chromatographed product                       ______________________________________                                         Absence of C═O                                                             17-OH             3612 cm.sup.-1                                               5-OH              3508 cm.sup.-1                                               Aromatic          1509 cm.sup.-1 - 1472 cm.sup.-1                              O--Si                                                                          ______________________________________                                    

Step C 3-(1,2-ethanediyl cyclic acetal) of 17β-acetyloxy-11β-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-Δ⁹ -estren-5α-o1-3-one

Using the procedure of (a) Step C of preparation 1, the product of Step B was reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate (6-4)), 2.58 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                C═O       1728 cm.sup.-1                                                   5-OH          3508 cm.sup.-1                                                   Aromatic      1508 cm.sup.-1                                                   O--Si                                                                   ______________________________________                                    

Step D 17β-acetyloxy-11β-[4-(8-hydroxy-octyl)-phenyl]-Δ⁴,9 -estradien-3-one

Using the procedure of (b) Step C of preparation 1, the product of Step C was reacted to obtained after chromatography on silica (eluant: cyclohexane-ethyl acetate (5-5), 1.2 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of O--Si                                                               OH                    3622 cm.sup.-1                                           C═O               1728 cm.sup.-1                                           dienone               1656 cm.sup.-1                                                                 1602 cm.sup.-1                                           Aromatic              1509 cm.sup.-1                                           ______________________________________                                    

PREPARATION 5 17β-acetyloxy-3-oxo-11β-Δ⁴,9 -estradiene undecanoic acid Step A 3-(1,2-ethanediyl cyclic acetal) of 11β-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-Δ⁹ -estrene-5-o1-3,17-dione

Using the procedure of Step A of preparation 1, 17.5 g of the epoxide of EP 0,057,115 (Example 7) and 500 ml of a 0.32M suspension in tetrahydrofuran of 11-(dimethyl-tert-.butylsilyloxy)-undecyl magnesium bromide (prepared by ICI Patent No. 85-100658) were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate (95-5 then 5-5)), 15.3 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                5-hydroxy     3510 cm.sup.-1                                                   17 keto       1733 cm.sup.-1                                            ______________________________________                                    

Step B (1,2-ethanediyl cyclic acetal) of 11β-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-Δ⁹ -estren-5α, 17β-diol-3-one

Using the procedure of Step B of preparation 1, 15.2 g of the product of Step A were reacted to obtain 14.863 g of the desired product, which was used as is for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17-OH                 3613 cm.sup.-1                                           5-OH                  3508 cm.sup.-1                                           O--Si                                                                          Intense aliphatic                                                              ______________________________________                                    

Step C (1,2-ethanediyl cyclic acetal) of 17β-acetyloxy-11β-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-Δ⁹ -estren-5α-o1-3-one

A mixture of 13.335 g of the product of Step B, 53 ml of pyridine and 26 ml of acetic anhydride was stirred for 4 hours 30 minutes at ambient temperature and was then cooled and neutralized by adding, over 45 minutes, sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness under vacuum to obtain 15 g of the desired product which was used as is for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                5-OH          3515 cm.sup.-1                                                   C═O       1728 cm.sup.-1                                            ______________________________________                                    

Step D 17β-acetoxy-11β-(11-hydroxy undecyl)-Δ⁴,9 -estradien-3-one

A mixture of 15 g of the product of Step C, 300 ml of methanol and 75 ml of 2N hydrochloric acid was stirred for 2 hours 45 minutes and then 20 ml of concentrated ammonia were added and the methanol was evaporated under vacuum. The mixture was extracted with ethyl acetate and the organic phase was washed with water saturated with sodium chloride, dried and evaporated to dryness under vacuum to obtain 12.75 g of product which was chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 8.37 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         free and associated OH 3613 cm.sup.-1                                          C═O                1729 cm.sup.-1                                          dienone                1654 cm.sup.-1                                                                 1601 cm.sup.-1                                          ______________________________________                                    

Step E 17β-acetoxyloxy-3-oxo-11β-Δ⁴,9 -estradiene-undecanoic acid

Using the procedure of Step C of preparation 1, 8.37 g of the product of Step D were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate (5-5)), 6.67 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Presence of acid in the OH region                                              ______________________________________                                         C═O           1728 cm.sup.-1                                                                 1712 cm.sup.-1                                               dienone           1654 cm.sup.-1                                                                 1600 cm.sup.-1                                               aliphatic very intense.                                                        ______________________________________                                    

PREPARATION 6 3,17-dioxo-11β-Δ⁴,9 -estradiene undecanoic acid Step A 11β-(11-hydroxy undecyl)-Δ⁴,9 -estradiene-3,17-dione

A mixture of 1 g of the product of Step A of preparation 5, 20 ml of methanol and 5 ml of 2N hydrochloric acid was stirred for 75 minutes at ambient temperature and the mixture was made alkaline to pH approx. 9 with concentrated ammonia, then was evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed with a saturated sodium chloride solution, dried and concentrated to dryness under reduced pressure. The dry extract was chromatographed on silica (eluant: cyclohexane-ethyl acetate (6-4)) to obtain 670 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      The presence of acid in the OH region                                          ______________________________________                                                OH     3623 cm.sup.-1                                                          17 keto                                                                               1736 cm.sup.-1                                                          dienone                                                                               1656 cm.sup.-1                                                                 1602 cm.sup.-1                                                   ______________________________________                                    

Step B 3,17-dioxo-11β-Δ⁴,9 -estradiene undecanoic acid

Using the procedure of Step C of preparation 2, 10.4 g of the product of Step A were reacted to obtain 12.4 g of the desired product which was used as is for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of alcohol                                                             ______________________________________                                         C═O               1736 cm.sup.-1                                                                 1709 cm.sup.-1                                           dienone               1656 cm.sup.-1                                                                 1601 cm.sup.-1                                           Presence of acid in the OH region.                                             ______________________________________                                    

PREPARATION 7 17β-hydroxy-3-oxo-17α-(1-propynyl)-11β-Δ⁴,9 -esterdiene undecanoic acid Step A 3,3-dimethyl ketal of 5α,10α-epoxy-Δ⁹,11 -estradiene-3,17-dione

To a solution of 5 kg of 3,3-dimethyl ketal-.sup.Δ4,9 -estradien-17-one (French Patent No. 1,514,086) in 25 liters of methylene chloride and 25 ml of pyridine, 430 g of hexachloroacetone and 1.3 liters of 200 volume hydrogen peroxide were added and the mixture was stirred for 24 hours at 16° to 18° C. and poured into a mixture of 1,400 kg of sodium thiosulfate and 50 liters of demineralized water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure to obtain 7.29 kg of the desired product which was used as is for the following step.

Step B 3,3-dimethyl ketal of 11β-(11-dimethyl tert-butyl silyloxy undecyl)-Δ⁹ -estrene-5β-o1-3,17-dione

To 600 ml of the magnesium derivative of bromo undecyloxy dimethyl tert-butyl silane (ICI Patent No. 85-100658) in 50 ml of tetrahydrofuran cooled to 0° C., there was added 1.58 g of cuprous chloride and the mixture was stirred for 30 minutes and cooled to -30° C. A solution of 18.17 g of the product of Step A in solution in 87 ml of tetrahydrofuran was added and the mixture was stirred for 3 hours and 30 minutes at ambient temperature, then poured into a solution of ammonium chloride at 0° C. The mixture was stirred for 10 minutes and extracted with ethyl acetate followed by methylene chloride. The organic phases were washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The 123 g of residue was chromatographed on silica (eluant: methylene chloride-ethyl acetate (9-1) with 1% of triethylamine) to obtain 5.19 g of the desired product used as is in the following step.

Step C 11β-(11-hydroxy undecyl)-17α-(1-propynyl)-Δ⁴,9 -estradiene-17β-o1-3-one

84 ml of butyl lithium in hexane (1.6 mol/liter) were cooled to -70° C. and slowly 84 ml of tetahydrofuran were added. Methyl acetylene was bubbled therethrough while maintaining the temperature at -50° C. and after 10 minutes, the temperature fell to the temperature fell to -70° C. The bubbling in was stopped and the mixture was stirred for 30 minutes at -70° C. 4.18 g of the product of Step B in solution in 80 ml of tetrahydrofuran were added and the temperature returned to ambient temperature. The mixture was stirred for 1 hour under these conditions and poured into a solution of ammonium chloride at 0° C. The mixture was extracted with ethyl acetate and then methylene chloride and the organic phases were washed, dried and evaporated to dryness under reduced pressure. The 6 g of residue were redissolved in 50 ml of ethanol and 10 ml of 2N hydrochloric acid and the mixture was stirred for 1 hour at ambient temperature and diluted with 100 ml of water. The mixture was extracted with chloroform and the organic phase was evaporated to dryness. The 4.9 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 2.25 g of the desired product.

    ______________________________________                                         Analysis for C.sub.32 H.sub.48 O.sub.3                                         ______________________________________                                         Calculated:    % C    79.95     % H  10.06                                     Found:                79.9           10.1                                      ______________________________________                                    

Step D 17β-acetyloxy-11β-(11-hydroxy undecyl)-17α-(1-propynyl)-Δ⁴,9 -estradien-3-one a) Diacetylation

A solution of 5.07 g of the product of Step C of Example 9 in 48 ml of pyridine, 1 g of 4-dimethylamino-pyridine and 17.6 ml of acetic anhydride was stirred for 18 hours at 20° C. and then 200 ml of ice were added all at once. The mixture was neutralized with a saturated sodium bicarbonate solution and stirred for 30 minutes followed by extraction with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 8 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 2.83 g of the desired product.

b) Mono-Saponification

A solution of 2.8 g of the diacetylated product in 28 ml of methanol with 0.7 g of potassium bicarbonate was heated to 70° C. for 90 minutes and then 100 ml of iced water were added. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness. The 2.6 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 1.18 g of the desired product used as is for the following step.

Step E 17β-acetyloxy-3-oxo-17α-(1-propynyl)-11β-Δ⁴,9 -estradiene undecanoic acid

To a solution of 460 mg of the product of Step A in 24 ml of acetone, 0.8 ml of a solution prepared from 57 ml of concentrated sulfuric acid, 67 g of chromic oxide and sufficient water to make to 250 ml were added over 1 hour at 0° C.

8 drops of methanol, 28 ml of water and 8 g of barium carbonate were added to the reaction solution at 0° C. and the mixture was stirred for 1 hour at 0° C. and filtered to remove the insoluble material. The filtrate was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure and the 384 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 198 mg of the desired product.

Step F 17β-hydroxy-3-oxo-17α-(1-propynyl)-11β-Δ⁴,9 -estradiene undecanoic acid

A solution of 722 mg of the product of Step B in 8 ml of a 1M solution of methanolic potassium hydroxide was stirred at room temperature for one hour and 10 g of ice, then 10 ml of normal hydrochloric acid were added all at once. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure to obtain 593 mg of the desired product used as is for the following step.

PREPARATION 8 11β-(12-hydroxy dodecyl)-Δ⁴,9 -estradiene-3,17-dione Step A 3-(1,2-ethanediyl cyclic acetal) of 11β-[[12-[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-dodecyl]-Δ.sup.9 -estrene-5α-o1-3,17-dione

Using the procedure of Step A of preparation 1, 2.97 g of the epoxide of European Patent No. 0,057,115 (Example 7) and 12 g of dodecanoxy dimethyl tert-butyl silane magnesium bromide (preparation 13) were reacted to obtain, after chromatography on silica (eluant: cyclohexane-ethyl acetate (6-4)), 5.24 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH            3510 cm.sup.-1                                                   CO            1733 cm.sup.-1                                                    ##STR38##     836 cm.sup.-1                                                   ______________________________________                                    

Step B 11β-(12-hydroxy-dodecyl-Δ⁴,9 -estradiene-3,17-dione

Using the procedure of Step A of Preparation 6, 5.2 g of the product of Step A were reacted and after chromatography on silica (eluant: cyclohexane-ethyl acetate (6-4)), 2.78 g of the desired product were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3625 cm.sup.-1                                                C═O          1736 cm.sup.-1 (17 acetate)                                   Dienone          1656 cm.sup.-1                                                                 1602 cm.sup.-1                                                ______________________________________                                    

PREPARATION 9 Phenethoxy dimethyl tert-buty silyl bromide

To a solution of 15 g of 4-bromophenethyl alcohol in 60 ml of tetrahydrofuran at 0° C. to 5° C., 10.6 g of imidazole were added followed by addition over 30 minutes of a solution of of 14.33 g of dimethyl tert-butyl chlorosilane in 20 ml of tetrahydrofuran at 0°±2° C. The mixture was diluted with 40 ml of tetrahydrofuran and was then stirred for 2 hours at ambient temperature and filtered to remove the insoluble material. The filtrate was evaporated to dryness under reduced pressure and the 32.89 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (95-5)), to obtain 24 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                   Absence of OH                                                                   ##STR39##                                                           ______________________________________                                    

PREPARATION 10 1-chloro-7-heptanol (used in Step A of Preparation 3)

A mixture of 44 g of heptane diol, 400 ml of concentrated hydrochloric acid, 150 ml of toluene and 50 ml of water was stirred for two and half hours at reflux. The toluene fraction was removed and 200 ml of toluene were added to the aqueous fraction and the mixture was heated for five hours at 85° C. to 90° C. The toluene was removed and 200 ml of toluene and 100 ml of concentrated hydrochloric acid were added to the aqueous phase. The mixture was heated for five hours, then cooled and the organic fraction was combined with the two preceding toluene fractions. The toluene fraction was washed with water, dried and evaporated to dryness under reduced pressure, then distilled at 70° C. under 0.5 mm of mercury to obtain 37 g of the desired product.

    ______________________________________                                         Analysis: C.sub.7 H.sub.15 Cl.sub.1 O; molecular weight                        ______________________________________                                         = 150.65                                                                       Calculated:                                                                             % C     55.81   % H   10.03 % Cl  23.53                               Found:           55.8          10.2        23.8                                ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Primary OH     3615 cm.sup.-1                                                  ______________________________________                                    

PREPARATION 11 Dimethyl tert-butyl silyl octyloxy bromobenzene STEP A Chlorohexyloxy dimethyl tert-butyl silyl

To a mixture of 40.93 g of 1-chlorohexanol, 42.9 g of imidazole and 102 ml of tetrahydrofuran, a solution of 56.07 g of dimethyl tert-butyl silyl chloride in 114 ml of tetrahydrofuran was added at 15° to 18° C. and the mixture was stirred for 15 hours at ambient temperature and then centrifuged to remove the precipitate. Chromatography on silica (eluant: cyclohexane-ethyl acetate (95-5)) obtained 74.28 g of the desired product.

STEP B Dimethyl tert-butyl silyl octyloxy bromobenzene a) Chlorohexyloxy dimethyl tert-butyl silyl magnesium

A solution of 74.82 g of the product of Step A in 300 ml of tetrahydrofuran was added to a suspension of 0.871 g of magnesium and 271 ml of tetrahydrofuran and the mixture was refluxed for 4 hours and cooled to obtain the desired magnesium derivative with a titer approximately 0.375 mol/liter

50 g of iodoethyl benzene (Preparation 12) in 500 ml of tetrahydrofuran were added at -70° C. over 15 minutes to 640 ml of the magnesium derivative solution and the mixture was stirred while allowing a return to ambient temperature and the stirring was continued for 15 hours. 500 ml of water saturated with ammonium chloride were added and the mixture was stirred for 15 minutes. The decanted organic phase was washed, dried and evaporated to dryness and the 101.3 g of residue were chromatographed on silica (eluant: cyclohexane) obtain 39.5 g of the desired product.

PREPARATION 12 1-p-bromophenethyl iodide STEP A 1-p-bromophenethyl alcohol

To a solution of 95.2 g of 4-bromophenyl acetic acid in 950 ml of tetrahydrofuran. 49 ml of 10M borane-dimethyl sulfide complex were added over 35 minutes at 15° to 20° C. and the mixture was refluxed over 20 minutes and maintained for 10 minutes, then cooled. 50 ml of water were added and the mixture was extracted with ethyl acetate and evaporated to dryness under reduced pressure. The 102 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (6-4)) to obtain the desired product.

Step B 1-p-bromophenethyl p-toluene sulfonate

To a solution of 41 g of the alcohol of Step A in 102 ml of pyridine, 77.72 g of tosyl chloride were added over 35 minutes at 5° C.±1° C. and the mixture was stirred for another 30 minutes at 5° C., then allowed to return to ambient temperature. 500 ml of of saturated sodium bicarbonate solution were added and the mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain 71.4 g of the desired product melting at 92° C.

Step C 1-p-bromophenethyl iodide

To a solution of 71.4 g of the p-toluene sulfonate of Step B in 1,400 ml of acetone, 45.12 g of sodium iodide were added and the mixture was heated to a slight reflux which was maintained for 2 hours, then cooled. The mixture was centrifuged to remove the precipitate which was washed with acetone. The filtrate was evaporated to dryness under reduced pressure and the 80.5 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (8-2)) to obtain 60.54 g of the desired product melting approximately at 40° C.

PREPARATION 13 Bromododecanoxy dimethyl tert-butyl silane

To a solution of 10 g of 12-bromo-1-decanol in 40 ml of tetrahydrofuran, 5.48 g of imidazole were added and over 10 minutes a solution of 7.058 g of dimethyl tert-butyl chlorosilane in 10 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble material was filtered off. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed on silica (eluant: cyclohexane-ethyl acetate (95-5)) to obtain 13.57 g of the desired product usable as is for Step A of Example 15.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Little or no OH                                                                ______________________________________                                         Probable O--Si  1257 cm.sup.-1                                                                  837 cm.sup.-1                                                 Intense aliphatic                                                              ______________________________________                                    

EXAMPLE 1 4-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11-yl)-N-methyl-N-benzene acetamide Step A 4-(17β-acetyloxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-N-methyl-N-isopropyl-benzene acetamide a) Oxidation

A solution of 3.3 g of the product of Step C of Preparation 1 in 200 ml of acetone was cooled to 0° C. and 6.36 ml of a solution prepared from 67 g of chromic oxide, 57 ml of sulfuric acid and demineralized water sufficient for 250 ml were added over 20 minutes at +2°-+3° C. and the mixture was stirred for 5 minutes. 4 ml of methanol and 16 g of barium carbonate were added and the mixture was stirred for one hour and permitted to return to ambient temperature. The mixture was filtered, washed with acetone and evaporated to dryness to obtain 3.282 g of residue.

b) Amidification

To a solution cooled to -10° C. of 3.282 g of the above product in 150 ml of methylene chloride, 3 ml of N-methyl morpholine and 3.3 ml of isobutyl chloroformate were added and the mixture was stirred for 30 minutes at -10° C. 3.3 ml of N-isopropyl methylamine were added and the temperature was allowed to rise. After stirring for 30 minutes, the mixture was poured into an iced sodium bicarbonate solution, stirred for 10 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness and the 7.6 g of residue were chromatographed on silica (eluant: methylene chloride-acetone (9-1)) to obtain 2.15 g of the desired product.

    ______________________________________                                         IR Spectrum: CHCl.sub.3 (on Nicolet)                                           ______________________________________                                         C═O         1728 cm.sup.-1 OAC                                             Dienone         1654 cm.sup.-1                                                                 1608 cm.sup.-1                                                 C═O         1624 cm.sup.-1 Tertiary amide                                  Aromatic        1509 cm.sup.-1                                                 ______________________________________                                    

Step B 4-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-N-methyl-N-isopropyl-benzene acetamide

A solution of 0.5 g of the product of Step A, 15 ml of methanol and 336 mg of potassium hydroxide was stirred for one hour and then cooled to 0° C. and neutralized by the addition of 7.4 ml of 2N hydrochloric acid. The mixture was extracted with methylene chloride and evaporated to dryness under reduced pressure. The 459 mg of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane (9-1)) to obtain 0.288 g of the desired product.

    ______________________________________                                         Analysis: C.sub.30 H.sub.39 NO.sub.3 ; molecular weight                        ______________________________________                                         = 461.65                                                                       Calculated:                                                                             % C     78.05   % H   8.52  % N   3.03                                Found:           77.8          8.6         3.1                                 ______________________________________                                         IR Spectrum: CHCl.sub.3 (on Nicolet)                                           ______________________________________                                                OH     3612 cm.sup.-1                                                          C═O                                                                               1653 cm.sup.-1                                                                 1623 cm.sup.-1                                                          Aromatic                                                                              1570 cm.sup.-1                                                                 1509 cm.sup.-1                                                   ______________________________________                                    

EXAMPLE 2 4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-N-methyl-N-isopropyl-benzene acetamide

To a solution of 1.045 g of the product of Step A of Example 1 in 20 ml of methanol, 2 g of palladium hydroxide with 20% magnesium oxide were added and the mixture was refluxed for 30 minutes then filtered off the catalyst. The filtrate was washed with methanol and evaporated to dryness under reduced pressure. The 1.03 g of residue were redissolved in 30 ml of methanol and 980 mg of potassium hydroxide pellets were added. The mixture was stirred for 45 minutes at ambient temperature and 50 g of ice and 20 ml of 2N hydrochloric acid were added. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The 1.1 g of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane (8-2)) to obtain 467 mg of the desired product.

    ______________________________________                                         Analysis: C.sub.30 H.sub.39 NO.sub.3 ; molecular weight                        ______________________________________                                         = 461.641                                                                      Calculated:                                                                             % C     78.05   % H   8.51  % N   3.03                                Found:           78.2          8.5         2.9                                 ______________________________________                                         IR Spectrum: CHCl.sub.3 (on Nicolet)                                           ______________________________________                                         OH                    3602 cm.sup.-1 + associated                              C═O               1620 cm.sup.-1                                                                 1580 cm.sup.-1 (ep.)                                     Aromatic              1513 cm.sup.-1                                                                 1501 cm.sup.-1 (max.)                                    ______________________________________                                    

EXAMPLE 3 N-butyl-3,17β-dihydroxy-11βΔ¹,3,5(10) -estratriene-pentanamide Step A N-butyl-3,17-dioxo-11β-Δ⁴,9 -estradien-pentanamide

To a solution of 3.4 g of the product of Step C of Preparation 2 in 64 ml of methylene chloride at -10° to -15° C., 3.25 ml of N-methyl morpholine were added dropwise followed by 3.8 ml of isobutyl chloroformate and the mixture was stirred for 30 minutes at -10° to -15° C. and then at this temperature, 4.1 of N-butylamine were added. The mixture was allowed to return to ambient temperature and after 40 mintues, 100 ml of a saturated sodium bicarbonate solution were added. The mixture was stirred for 10 minutes and the decanted aqueous phase was extracted with methylene chloride. The organic phase was washed with a saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 7 g of residue were chromatographed on silica (eluant: methylene chloride-acetone (8-2)) and after evaporation to dryness, 2.3 g of the desired product were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17 ketone        1736 cm.sup.-1                                                NH               3349 cm.sup.-1                                                Amide II         1519 cm.sup.-1                                                Dienone + C═C                                                                               1602 cm.sup.-1                                                                  868 cm.sup.-1                                                Dienone + amide  1658 CM.sup.-1                                                ______________________________________                                    

Step B 3-acetyloxy-N-butyl-17-oxo-11β-Δ¹,3,5(10) -estratrien-pentanamide

To a solution of 2.3 g of the product of Step A in 25 ml of methylene chloride at 0° C. to -5° C., 2.5 ml of acetic anhydride and 1.25 ml of acetyl bromide were added and the mixture was stirred for 80 minutes at ambient temperature and then poured into a mixture of 150 ml of saturated sodium bicarbonate solution and 50 g of ice. The mixture was stirred for 15 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and washed twice with toluene to obtain 2.9 g of product which was chromatographed on silica (eluant: methylene chloride-acetone (9-1)) to obtain 2.3 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                                             1610 cm.sup.-1                             Aromatics                           1582 cm.sup.-1                                                                 1494 cm.sup.-1                                                  NH═        3349 cm.sup.-1                             Secondary amide      Amide II       1518 cm.sup.-1                                                  C═O        1661 cm.sup.-1                             17 ketone                           1736 cm.sup.-1                                                                 1408 cm.sup.-1                             Acetate                             1760 cm.sup.-1                                                                 1770 cm.sup.-1                             Methyl (acetate)                    1371 cm.sup.-1                             ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-11β-Δ¹,3,5(10) -estratrien-pentanamide

To a solution of 1.85 g of the product of Step B in 16 ml of methanol at 0° to 5° C., 192 mg of sodium borohydride were added and the mixture was stirred for 30 minutes. 640 mg of potassium hydroxide pellets were added and after 20 minutes at ambient temperature, 50 g of iced water (1-1) were added and the pH was adjusted to 4-5 with 2N hydrochloric acid. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The organic phase was evaporated to dryness and the residue was chromatographed on silica (eluant: methylene chloride-acetone (75-25)) to obtain 1.56 g of the desired crude product. The latter was dissolved in 5 ml of methanol and 75 ml of methylene chloride were added. The mixture was filtered and concentrated to crystallization. The mixture was refrigerated for 3 hours, and centrifuged to obtain 1.33 g of the desired product melting at ≃100° C. (approximately) with a specific rotation of [α]_(D) +117.5°±2° (c=1% in EtOH).

    ______________________________________                                         Analysis: C.sub.27 H.sub.41 O.sub.3 N; molecular weight                        ______________________________________                                         = 427.63                                                                       Calculated:                                                                             % C     75.83   % H   9.66  % N   3.27                                Found:           75.5          9.8         3.2                                 ______________________________________                                         IR Spectrum: Nujol                                                             ______________________________________                                         Strong absorption in the NH/OH region                                                                        3389 cm.sup.-1                                                                 3202 cm.sup.-1                                   C═O Amide                 1653 cm.sup.-1                                   Amide II                      1532 cm.sup.-1                                                                 1610 cm.sup.-1                                   Aromatics                     1582 cm.sup.-1                                                                 1502 cm.sup.-1                                   ______________________________________                                    

EXAMPLE 4 N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratrien-pentanamide Step A N-butyl-3,17-dioxo-N-methyl-11β-Δ⁴,9 -estradiene-pentanamide

Using the procedure of Step A of Example 3, 3 g of the acid of Step C of Preparation 2 and 4.1 ml of N-methyl butylamine instead of the N-butylamine were reacted to obtain 2.82 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of acid                                                                ______________________________________                                         17 keto           1736 cm.sup.-1                                               Tertiary amide    1630 cm.sup.-1                                               Ketone conjugated with                                                                           1642 cm.sup.-1                                               the tertiary amide                                                             C═C           1603 cm.sup.-1                                               ______________________________________                                    

Step B 3-acetyloxy-N-butyl-N-methyl-17-oxo-11β-Δ¹,3,5(10) -estratriene-pentanamide

Using the procedure of Step B of Example 3, 2.8 g of the product were reacted to obtain 2.62 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17 keto + phenolic acetate                                                                        1736 cm.sup.-1                                              Tertiary amide     1627 cm.sup.-1                                              Aromatic           1586 cm.sup.-1                                                                 1493 cm.sup.-1                                              ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene-pentanamide

Using the procedure of Step C of Example 3, 2.5 g of the product of Step B were reacted to obtain 2.026 g of the desired product. An analytical sample was prepared by dissolving 1.8 g of the product in 100 ml of ethyl acetate at 60° C. and after filtration, the filtrate was concentrated to the start of crystallization, then stirred for 3 hours at 0° C., and centrifuged to obtain 1.58 g of the desired product melting at approximately 165° C. and with a specific rotation of [α]_(D) =+113°±2° (c=1% in EtOH).

    ______________________________________                                         Analysis: C.sub.28 H.sub.43 O.sub.3 N; molecular weight                        ______________________________________                                         = 441.66                                                                       Calculated:                                                                             % C     76.15   % H    9.81 % N   3.17                                Found:           76.0          10.0        3.0                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Tertiary amide ketone                                                                            1625 cm.sup.-1                                               OH                3601 cm.sup.-1                                               Aromatic          1585 cm.sup.-1 -1499 cm.sup.-1                               ______________________________________                                    

EXAMPLE 5 N-butyl-3,17β-dihydroxy-11β-Δ¹,3,5(10) -estratriene-heptanamide Step A N-butyl-3,7-dioxo-11β-estra-Δ⁴,9 -estradiene heptanamide

Using the procedure of Step A of Example 3, 2.6 g of the acid of Step C of Preparation 3 were reacted to obtain 1.845 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of OH                                                                  ______________________________________                                         17 keto             1736 cm.sup.-1                                                                 1659 cm.sup.-1                                             Dienone + amide     1602 cm.sup.-1                                                                               for C═C                                                       864 cm.sup.-1                                             NH                  3450 cm.sup.-1                                             Amide II            1519 cm.sup.-1                                             ______________________________________                                    

Step B 3-acetyloxy-N-butyl-17-oxo-11β-Δ¹,3,5(10) -estratriene-heptanamide

Using the procedure of Step B of Example 3, 2.025 g of the product of Step A were reacted to obtain 1.95 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O        1735 cm.sup.-1                                                  C═O Amide  1660 cm.sup.-1                                                  Amide II       1518 cm.sup.-1                                                  NH              345 cm.sup.-1                                                  ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-11β-Δ¹,3,5(10) -estratriene-heptanamide

Using the procedure of Step C of Example 3, 1.68 g of the product of Step B were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone (8-9)), 1.277 g of the desired product. A sample for analysis was prepared by crystallization of 1.2 g of the crude product in ethyl acetate to obtain 1.04 g of the desired product melting at approximately 139° C. and having a specific rotation of [α]_(D) =+113°±2° (c=1% in ethanol).

    ______________________________________                                         Analysis: C.sub.29 H.sub.45 O.sub.3 N; molecular weight                        ______________________________________                                         = 455.65                                                                       Calculated:                                                                             % C     76.44   % H    9.95 % N   3.07                                Found:           76.5          10.1        3.0                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH + associated           3604 cm.sup.-1                                       NH                        3448 cm.sup.-1                                       C═O                   1657 cm.sup.-1                                       Amide II                  1522 cm.sup.-1                                                                 1620 cm.sup.-1                                                                 1609 cm.sup.-1                                       Aromatic                  1584 cm.sup.-1                                                                 1499 cm.sup.-1                                       ______________________________________                                    

EXAMPLE 6 N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene-heptanamide Step A N-butyl-3,17-dioxo-N-methyl-11β-Δ⁴,9 -estradiene-heptanamide

Using the procedure of Step A of Example 5, 3.04 g of the acid of Step C of Preparation 3 and 3.8 ml of N-methyl butylamine was reacted to obtain 3 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of OH                                                                  ______________________________________                                         17 keto        1736 cm.sup.-1                                                  C═O complex                                                                               1656 cm.sup.-1 (conjugated ketone)                                             1629 cm.sup.-1 (tertiary amide)                                 C═C        1603 cm.sup.-1                                                  ______________________________________                                    

Step B 3-acetyloxy-N-butyl-N-methyl-17-oxo-11β-Δ¹,3,5(10) -estratriene-heptanamide

Using the procedure of Step B of Example 5, 2.95 g of the product of Step A were reacted to obtain 2.7 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                          1760 cm.sup.-1 (ep.) phenolic OAC region                      C═O          1736 cm.sup.-1 (max) 17 keto                                                   1627 cm.sup.-1 Amide III                                      Aromatic         1585 cm.sup.-1 (ep.)                                                           1493 cm.sup.-1 (F)                                            ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene-heptanamide

Using the procedure of Step C of Example 5, 2.6 g of the product of Step B were reacted to obtain 2.067 g of the desired product. A sample for analysis was prepared by crystallizing 1.8 g of the product from chloroform to obtain 1.697 g of the desired product melting at 110° C. and having a specific rotation of [α]_(D) =106.5°±2° (c=1% in ethanol).

    ______________________________________                                         Analysis: C.sub.30 H.sub.47 O.sub.3 N; molecular weight                        ______________________________________                                         = 469.68                                                                       Calculated:                                                                             % C     76.71   % H   10.09 % N   2.98                                Found:           76.4          10.03       2.9                                 ______________________________________                                    

EXAMPLE 7 N-butyl-4-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-N-methyl benzene octanamide Step A N-butyl-N-methyl-4-[17β-acetyloxy-3-oxo-11β-Δ⁴,9 -estradien-11β-yl]-benzene octanamide a) 17β-acetoxy-3-oxo-11β-Δ⁴,9 -estradiene-benzene octanoic acid

Using the procedure of Step C of Preparation 2, 970 mg of the product of Step D of Preparation 4 were reacted to obtain 1.219 g of the desired product which was used as is for the amidification.

b) Amidification

Using the procedure of Step A of Example 3, 1.219 g of the above product and 1.1 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate (5-5)), 842 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of acid                                                                ______________________________________                                         C═O             1728 cm.sup.-1 (OAC)                                       Aromatic            1509 cm.sup.-1                                             Dienone + Amide III 1652 cm.sup.-1                                                                 1628 cm.sup.-1                                             ______________________________________                                    

Step B N-butyl-4-[17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl]-N-methyl benzene octanamide

Using the procedure of Step B of Example 1, 716 mg of the product of Step A were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate (5-5)), 508 mg of the desired product with a specific rotation of [α]_(D) =+169°±3° (c=0.5% in EtOH).

    ______________________________________                                         Analysis: C.sub.37 H.sub.53 NO.sub.3 ; molecular weight                        ______________________________________                                         = 559.79                                                                       Calculated:                                                                             % C     79.38   % H   9.54  % N   2.5                                 Found:           79.2          9.7         2.4                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH + Associated    3612 cm.sup.-1                                              Dienone + tertiary amide                                                                          1628 cm.sup.-1                                                                 1643 cm.sup.-1                                              Aromatic           1608 cm.sup.-1                                              ______________________________________                                    

EXAMPLE 8 N-butyl-4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11-yl)-N-methyl benzene octanamide Step A N-butyl-4-[3,17-diacetyloxy-Δ¹,3,5(10) -estratrien-11β-yl]-N-methyl benzene octanamide

To a solution of 293 mg of the product of Step A of Example 7 in 3 ml of methylene chloride, there was added at 0° C. to 5° C. 0.15 ml of acetyl bromide and 0.3 ml of acetic anhydride, and the mixture was stirred for 2 hours at ambient temperature and then poured into a saturated sodium bicarbonate solution. The mixture was stirred for 30 minutes and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under vacuum. The 300 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (7-3)) to obtain 217 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                               1755 cm.sup.-1                                           C═O               1728 cm.sup.-1 OAC                                                             1627 cm.sup.-1 Tertiary amide                            Aromatic at 11        1509 cm.sup.-1                                           Aromatic A ring       1494 cm.sup.-1                                           ______________________________________                                    

Step B N-Butyl-4-[3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-N-methyl benzene octanamide

At ambient temperature: 471 mg of the product of Step A in solution in 3.65 ml of methanolic potassium hydroxide was stirred for 40 minutes and then ice was added followed by 2.5 ml of 2N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness under vacuum. The 460 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 264 mg of the desired product with a specific rotation of [α]_(D) =+20°±2° (c=0.5% in EtOH).

    ______________________________________                                         Analysis: C.sub.37 H.sub.53 O.sub.3 N; molecular weight                        ______________________________________                                         = 559.79                                                                       Calculated:                                                                             % C     79.38   % H   9.54  % N   2.5                                 Found:           79.8          9.6         2.3                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH              3605 cm.sup.-1 + Associated                                    C═O         1621 cm.sup.-1 Tertiary amide                                  Aromatic        1583 cm.sup.-1                                                                 1500 cm.sup.-1                                                 ______________________________________                                    

EXAMPLE 9 N,N-dimethyl-17β-hydroxy-3-oxo-11β-Δ⁴,9 -estradiene-undecanamide Step A N,N-dimethyl-17β-acetyloxy-3-oxo-11β-Δ⁴,9 -estradiene-undecanamide

Using the procedure of Step A of Example 3, 2.7 g of the product of Step E of Preparation 5 and 2.28 g of dimethylamine in solution in 20 ml of tetrahydrofuran were reacted to obtain 1.6 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of acid                                                                ______________________________________                                         OAC               1728 cm.sup.-1                                               Dienone + Amide III                                                                              1336 cm.sup.-1                                                                 1603 cm.sup.-1                                               ______________________________________                                    

Step B N,N-dimethyl-¹⁷β -hydroxy-3-oxo-11β-Δ4,9-estradiene-undecanamide

Using the procedure of Step B of Example 1, 780 mg of the product of Step A were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone (8-2)), 485 mg of the desired product with a specific rotation of [α]_(D) =-21.5°±2.5° (c=0.35% in EtOH).

    ______________________________________                                         Analysis: C.sub.31 H.sub.49 NO.sub.3 ; molecular weight                        ______________________________________                                         = 483.74                                                                       Calculated:                                                                             % C     76.97   % H   10.21 % N   2.89                                Found:           77.0          10.2        2.7                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3616 cm.sup.-1                                                Amide III        1640 cm.sup.-1 (complex)                                      Dienone          1604 cm.sup.-1 C═O                                                          964 cm.sup.-1 C═C                                        ______________________________________                                    

EXAMPLE 10 N,N-dimethyl-3,17β-dihydroxy-11β-Δ¹,3,5(10) -estratriene-undecanamide Step A 3,17β-diacetyloxy-N,N-dimethyl-11β-Δ¹,3,5(10) -estratriene-undecanamide

Using the procedure of Step B of Example 3, 697 mg of the product of Step A of Example 9 were reacted to obtain 660 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of dienone                                                             ______________________________________                                         Acetate            1726 cm.sup.-1                                                                 1745 cm.sup.-1 (ep.)                                        Amide III          1632 cm.sup.-1                                              Aromatic           1494 cm.sup.-1                                              ______________________________________                                    

STEP B 3,17β-dihydroxy-N,N-dimethyl-11β-Δ¹,3,5(10) -estratriene-undecanamide

Using the procedure of Step B of Example 1 and isolating the product by crystallization in isopropanol, there were obtained 369 mg of the desired product melting at 130° C. and a specific rotation of [α]_(D) =+100°±2° (c=0.95% in EtOH).

    ______________________________________                                         Analysis: C.sub.31 H.sub.49 O.sub.3 N; molecular weight                        ______________________________________                                         = 483.74                                                                       Calculated:                                                                             % C     76.97   % H   10.21 % N   2.89                                Found:           77.0          10.4        2.7                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH + Associated   3605 cm.sup.-1                                               Amide III         1627 cm.sup.-1                                               Aromatic          1528 cm.sup.-1 -1498 cm.sup.-1                               ______________________________________                                    

EXAMPLE 11 N-butyl-17β-hydroxy-3-oxo-11β-Δ⁴,9 -estradiene-undecanamide STEP A 17β-acetyloxy-N-butyl-3-oxo-11β-Δ⁴,9 -estradiene-undecanamide

Using the procedure of Step A of Example 3, 6.67 g of the product of Step E of Preparation 5 were reacted to obtain, after chromatography on silica (eluant: cyclohexane-ethyl acetate (1-1)), 6.911 g of the desired product. A second chromatography of 3.443 g of the product with the same eluant yielded 2.898 g of the purified product.

    ______________________________________                                         Analysis: C.sub.35 H.sub.55 O.sub.4 N; molecular weight                        ______________________________________                                         = 553.75                                                                       Calculated:                                                                              % C 75.9   % H 10.01  % N 2.52                                       Found:    75.6       10.1       2.7                                            ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Little or no acid                                                               ##STR40##          3450 cm.sup.-1                                             Amide II            1519 cm.sup.-1                                             CO                  1657 cm.sup.-1                                             Acetate             1728 cm.sup.-1                                                                 1255 cm.sup.-1                                             Dienone             1657 cm.sup.-1                                                                 1601 cm.sup.-1                                             ______________________________________                                    

Step B N-butyl-17β-hydroxy-3-oxo-11β-Δ⁴,9 -estradiene-undecanamide

0.5 g of the product of Step A, 5 ml of methanol and 280 mg of potassium hydroxide pellets were stirred for 40 minutes at ambient temperature and 20 ml of ice were added. The mixture was neutralized with 2.5 ml of 2N hydrochloric acid and was extracted with ethyl acetate to obtain after evaporation to dryness 509 mg of product. The latter was chromatographed on silica (eluant: cyclohexane-ethyl acetate (1-1)) to obtain 287 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH            3612 cm.sup.-1                                                   ═C--NH    3450 cm.sup.-1                                                   Amide II      1518 cm.sup.-1                                                   C═O       1657 cm.sup.-1                                                                           (secondary amide +                                                             dienone)                                               ______________________________________                                         Analysis: C.sub.33 H.sub.53 NO.sub.3 ; molecular weight                        ______________________________________                                         = 511.8                                                                        Calculated:                                                                             % C     77.45   % H   10.44 % N   2.74                                Found:           77.1          10.7        2.7                                 ______________________________________                                    

EXAMPLE 12 N-butyl-3,17β-dihydroxy-11β-Δ¹,3,5(10) -estratriene-undecan-amide STEP A 3,17β-bis(acetyloxy)-N-butyl-11β-Δ¹,3,5(10) -estratriene-undecanamide

Using the procedure of Step B of Example 3, 3 g of the product of Step A of Example 11 were reacted to obtain 3.66 g of crude product used as is for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                          ##STR41##      1749 cm.sup.-1 (ep.) 1726 cm.sup.-1 (max)                      Acetate         1254 cm.sup.-1 (F)                                              ##STR42##                                                                     ______________________________________                                    

STEP B N-butyl-3,17β-dihydroxy-11β-Δ¹,3,5(10) -estratrien-undecanamide

To a solution of 2.96 g of the product of Step A in 74 ml of methanol there was added 8.9 ml of a solution of 6 ml of a 11 g % ml methanolic potassium hydroxide and the mixture was stirred for 2 hours at 60° C. and then was iced, and neutralized with 15 ml of normal hydrochloric acid. The methanol was distilled and the mixture was diluted with aqueous saturated sodium chloride and extracted with ethyl acetate. After evaporation to dryness, the 2.7 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (5-5)) to obtain 1.841 g of the desired product. A sample for analysis was prepared by a second chromatogrphy under the same conditions to obtain 1.547 g of the desired compound with a specific rotation of [α]_(D) =+85°±3° (c=0.5% in ethanol).

    ______________________________________                                         Analysis: C.sub.33 H.sub.53 NO.sub.3 ; molecular weight                        ______________________________________                                         = 511.75                                                                       Calculated:                                                                             % C     77.45   % H   10.43 % N   2.73                                Found:           77.5          10.7        2.9                                 (lost under vacuum 1.5% at 100° C.)                                     ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         HO                        3605 cm.sup.-1                                       ═C--NH                3448 cm.sup.-1                                       C═O Amide             1657 cm.sup.-1                                       Amide II                  1524 cm.sup.-1                                                                 1620 cm.sup.-1                                       Aromatic                  1582 cm.sup.-1                                                                 1498 cm.sup.-1                                       ______________________________________                                    

EXAMPLE 13 N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene-undecanamide STEP A N-butyl-3,17β-bis-[(tetrahydro-2H-pyrann-2-yl)-oxo]-11β-Δ.sup.1,3,5(10) -estratriene-undecanamide

A solution of 266 mg of the product of Step B of Example 12, 6.7 ml of sulfuric ether 4.7 ml of dihydropyran and 5 mg of p-toluene sulfonic acid was stirred for 90 minutes and 1 ml of triethylamine was added. The mixture was washed with a sodium bicarbonate solution, then with a saturated sodium chloride solution, dried and evaporated to dryness. The 400 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (7-3)) to obtain 286 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of OH                                                                   ##STR43##                                                                     NH                      3450 cm.sup.-1                                         Amide II                1518 cm.sup.-1                                         CO                      1660 cm.sup.-1                                         ______________________________________                                    

Step B N-butyl-3,17β-bis-[(tetrahydro-2H-pyrann-2-yl)-oxy]-N-methyl-11β-Δ¹,3,5(10) -estratriene-undecanamide

920 mg of the product of Step A with 14 ml of tetrahydrofuran, 2.27 g of tetrabutylammonium bromide, 1.9 g of powdered potassium hydroxide and 14 ml of methyl iodide were stirred for 18 hours at 50° C. under pressure. After refrigeration, the insoluble material was filtered off and washed with 5 changes of 50 ml of tetrahydrofuran. The organic phase was evaporated to dryness under reduced pressure and the 3.4 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate triethylamine (70-30-0.2)) to obtain 850 mg of the desired product used as is for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         No secondary amine                                                             C═O                    1627 cm.sup.-1                                      OTHP                       Probable                                                                       1605 cm.sup.-1                                      Aromatic                   1572 cm.sup.-1                                                                 1497 cm.sup.-1                                      ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene undecanamide

850 mg of the product of Step B, 35 ml of methanol and 3.5 ml of 2N hydrochloric acid were stirred for 1 hour at ambient temperature and the pH was adjusted to 5-6 with 5 ml of concentrated ammonia. The mixture was extracted with methylene chloride, and the organic phase was washed with water, then with a saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 638 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (6-4)) to obtain 520 mg of the desired product. A sample of 618 mg of product (98 mg from an earlier preparation was joined to the 520 mg obtained above) was chromatographed on silica (eluant: methylene chloride-acetone (9-1)) to obtain 527 mg of purified product with a specific rotation of [α]_(D) =90.5°±2° (c=1% in EtOH).

    ______________________________________                                         Analysis: C.sub.34 H.sub.55 O.sub.3 N; molecular weight = 525.82               Calculated:                                                                               % C    77.67    % H  10.54 % N  2.66                                Found:            77.0          10.6       2.6                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of Amide II                                                            HO                3606 cm.sup.-1 (+ associated)                                C═O           1620 cm.sup.-1                                               Aromatic          1582 cm.sup.-1                                                                 1498 cm.sup.-1                                               ______________________________________                                    

EXAMPLE 14 N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene undecanamide Step A 17β-acetyloxy-N-butyl-N-methyl-3-oxo-11β-Δ⁴,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 88.5 g of the acid of Step E of Preparaton 5 and 88.5 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: hexane-ethyl acetate (5-5)) 67.3 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OAC                    1728 cm.sup.-1                                                                 1255 cm.sup.-1                                          Dienone                 864 cm.sup.-1                                          Dienone + Amide III    1628 cm.sup.-1                                                                 1655 cm.sup.-1                                          ______________________________________                                    

Step B 3,17β-bis(acetyloxy)-N-butyl-N-methyl-11β-Δ¹,3,5(10) -estratriene undecanamide

Using the procedure of Step B of Example 3, 67.3 g of the product of Step A were reacted and the dry extract obtained was not chromatographed to obtain 75 g of the desired product used as is for the following step.

Step C N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene undecanamide

74 g of the product of Step B, 1.850 liters of methanol and 222 ml of methanolic potassium hydroxide at 11 g % ml was stirred for 2 hours at 60° C. and cooled to 0° C. to +5° C. The pH was adjusted to 4-5 by the addition of hydrochloric acid and the methanol was distilled under reduced pressure. The mixture was extracted with methylene chloride and the organic extracts were washed with water, dried and evaporated to dryness under reduced pressure to obtain 65.8 g of resin to which was added 1.7 g made in a previous preparation.

Purfication

67.5 g of crude product were crystallized from 350 ml of ethyl acetate and the mixture was centrifuged at 0° to +5° C. to obtain 45 g of the desired product to which was added 3 g of once-purified product obtained from the mother liquors.

The 48 g of product were crystallized from 4 volumes of ethyl acetate to obtain 46.1 g of the desired product melting at 127° C. and with a specific rotation of [α]_(D) =+90.1°±2° (c=1% in EtOH).

    ______________________________________                                         Analysis: C.sub.34 H.sub.55 O.sub.3 N; molecular weight                        ______________________________________                                         = 525.82                                                                       Calculated:                                                                               % C    77.67    % H  10.54 % N  2.66                                Found:            77.9          10.6       2.6                                 ______________________________________                                    

EXAMPLE 15 17β-hydroxy-N-methyl-N-isoprolyl 3-oxo-11β-Δ⁴,9 -estra-diene undecanamide Step A N-isopropyl-3,17-dioxo-N-methyl-11β-Δ⁴,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 610 mg of the acid of Preparation 6 and 0.73 ml of N-methyl N-isopropylamine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone (9-11)), 455 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17 keto               1736 cm.sup.-1                                           Dienone               1656 cm.sup.-1                                           Tertiary Amide        1621 cm.sup.-1                                           ______________________________________                                    

Step B 17β-hydroxy N-methyl-N-isopropyl 3-oxo-11β-Δ⁴,9 estradiene undecanamide

To a solution of 1.18 g of the product of Step A in 18 ml of tetrahydrofuran, there were added at 0° to -5° C. 707 mg of triterbutoxy aluminium-lithium hydride and the mixture was stirred for 1 hour at 0° to -5° C. and poured into 80 gms of a mixture of equal parts of ice and a saturated ammonium chloride solution. The mixture was stirred for 5 minutes and extracted three times with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The 1.14 g of residue and 256 mg obtained from a preceding preparation were chromatographed on silica (eluant: methylene chloride-acetone (9-1)) to obtain 640 mg of the desired product with a specific rotation of [α]_(D) =-43°±2.5° (c=0.4% in ethanol).

    ______________________________________                                         Analysis: C.sub.33 H.sub.53 O.sub.3 N; molecular weight = 511.75               Calculated:                                                                               % C    77.44    % H  10.44 % N  2.74                                Found:            77.6          10.7       2.7                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH            3613 cm.sup.-1                                                                 1650 cm.sup.-1 Dienone                                           C═O       1621 cm.sup.-1 + Tertiary Amide                                  ______________________________________                                    

EXAMPLE 16 3,17β-dihydroxy-N-methyl-N-isopropyl-11β-Δ¹,3,5(10) -estratriene undecanamide Step A 3-acetyloxy-N-isopropyl-17-oxo-N-methyl-11βΔ¹,3,5(10) estratriene undecanamide

Using the procedure of Step B of Example 3, 360 mg of the product of Step A of Example 15 were reacted to obtain after chromatography over silica (eluant: methylene chloride-acetone (95-5)) 310 mg of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Tertiary amide        1621 cm.sup.-1                                           Phenol acetate        1760 cm.sup.-1                                                                 1765 cm.sup.-1                                           17 keto               1735 cm.sup.-1                                           Aromatic              1493 cm.sup.-1                                           ______________________________________                                    

STEP B N-isopropyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) estratriene undecanamide

Using the procedure of Step C of Example 3, 272 mg of the product of Step A were reacted to obtain after chromatography (eluant: methylene chloride-acetone (9-1)), 195 mg of the crude expected product. The said product and 460 mg of product from a previous preparation were purified by passing three times over silica (eluant: acetonitrile) to obtain 460 mg of product which was chromatographed again over silica (eluant: methylene chloride-acetone (9-1)) to obtain 432 mg of the desired product with a specific rotation of [α]_(D) =+85° C. ±2° (c=1% in EtOH).

    ______________________________________                                         Analysis: C.sub.33 H.sub.53 O.sub.3 N; molecular weight = 511.75               Calculated:                                                                               % C    77.44    % H  10.44 % N  2.74                                Found:            77.4          10.7       2.6                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3606 cm.sup.-1 + associated                                   C═O          1618 cm.sup.-1                                                                 1583 cm.sup.-1                                                Aromatic         1498 cm.sup.-1                                                ______________________________________                                    

EXAMPLE 17 N-benzyl-17β-hydroxy-N-methyl-3-oxo-11β-Δ⁴,9 -estradiene undecanamide Step A N-benzyl-17β-acetoxy-N-methyl-3-oxo-11β-Δ⁴,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 2.1 g of the acid of Step E of Preparation 5 and 2.2 ml of benzyl methylamine were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl acetate (1-1)), 1.82 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O      1728 cm.sup.-1 (OAC)                                                           1645 cm.sup.-1 (III amide + Dienone)                              C═C       864 cm.sup.-1 (def.)                                             Aromatic     1496 cm.sup.-1                                                    ______________________________________                                    

Step B N-benzyl-17β-hydroxy-N-methyl-3-oxo-11β-Δ⁴,9 -estradiene undecanamide

Using the procedure of Step B of Example 1, 1 g of the product of Step A were reacted to obtain 670 mg of the desired product.

    ______________________________________                                         Analysis: C.sub.37 H.sub.53 O.sub.3 N; molecular weight                        ______________________________________                                         = 559.79                                                                       Calculated:                                                                              % C 79.39 % H 9.54    % N 2.5                                        Found:    79.3      9.7         2.4                                            ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         CO           1603 cm.sup.-1                                                     ##STR44##   1642 cm.sup.-1 (dienone + amide III)                              CC            863 cm.sup.-1                                                    Aromatic     1496 cm.sup.-1                                                    ______________________________________                                    

EXAMPLE 18 N-benzyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) estratriene undecanamide Step A 3,17β-diacetyloxy-N-benzyl-N-methyl-11β-Δ¹,3,5(10) -estratriene undecanamide

To a solution of 829 mg of the product of Step A of Example 17 in 8 ml of methylene chloride cooled to 0° to +5° C., 0.6 ml of acetic anhydride and 0.3 ml of acetyl bromide were added and the mixture was stirred for 2 hours, then poured into 60 g of a mixture of ice and a saturated solution of sodium bicarbonate (1-1). The mixture was stirred for 30 minutes and the decanted aqueous phase was extracted with methylene chloride. The organic phase was washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure The residue was chromatographed on silica (eluant: cyclohexane-AcOEt (75-25)) to obtain 760 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Phenol acetate       1767- 1752 cm.sup.-1                                      Acetate in position 17                                                                              1727 cm.sup.-1                                            C═O amide III    1632 cm.sup.-1                                                                 1494 cm.sup.-1                                            Aromatics            1585 cm.sup.-1                                            ______________________________________                                    

Step B N-benzyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene undecanamide

630 mg of the product of Step A, 13 ml of methanol and 910 mg of potassium hydroxide pellets were stirred for 1 hour at ambient temperature and the pH was adjusted to 4-5 by the addition of 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride and evaporated to dryness under reduced pressure. The 555 mg of residue were chromatographed over silica (eluant: methylene chloride-acetone (9-1)) to obtain 390 mg of the desired product with a specific rotation of [α]_(D) =+85.5°±2° (c=0.9% in EtOH).

    ______________________________________                                         Analysis: C.sub.37 H.sub.53 O.sub.3 N; molecular weight = 559.79               Calculated:                                                                               % C    79.38    % H  9.54  % N  2.5                                 Found:            79.5          9.6        2.4                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH              3605 cm.sup.-1 Free and associated                             C═O Amide III                                                                              1627 cm.sup.-1                                                                 1583 cm.sup.-1                                                 Aromatic        1497 cm.sup.-1                                                 ______________________________________                                    

EXAMPLE 19 N-[2-(dimethylamino)-ethyl]-17β-hydroxy-N-methyl-3-oxo-11β-.DELTA.⁴,9 -estradiene undecanamide Step A N-[2-dimethylamino)-ethyl]-17β-acetyloxy-N-methyl-3-oxo-11β-.DELTA.⁴,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 500 mg of the product of Step E of Preparation 5, 0.5 ml of N-N-N-trimethyl ethylenediamine were reacted to obtain after chromatography over silica (eluant: toluene-triethylamine (8-2)), 380 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Acetate                1729 cm.sup.-1                                                                 1255 cm.sup.-1                                          Dienone + Amide III    1644 cm.sup.-1                                          C═C                1604 cm.sup.-1                                          Bohlmann bands.                                                                ______________________________________                                    

Step B N-[2-(dimethylamino)-ethyl]-17β-hydroxy-N-methyl-3-oxo-11β-.DELTA.⁴,9 -estradiene undecanamide

800 mg of the product of Step A, 8 ml of methanol and 500 mg of potassium hydroxide pellets were stirred for 1 hour at ambient temperature and the mixture was concentrated to half-volume and a water and ice mixture was added. The mixture was extracted with ethyl acetate and the organic phase was washed with water, then with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 645 mg of residue were chromatographed first over silica (eluant: ethyl acetate-isopropanol-ammonia (80-20-2)), then a second time (eluant: ethyl acetate-triethylamine (6-4)) to obtain 526 mg of the desired product with a specific rotation of [α]_(D) =-26°±1.5° (c=0.7% in EtOH)

    ______________________________________                                         Analysis: C.sub.34 H.sub.56 O.sub.3 N.sub.2                                    ______________________________________                                         Calculated:                                                                              % C 75.51 % H 10.44   % N 5.18                                       Found:    75.3      10.6        5.2                                            ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Presence of OH and of Bohlmann band                                             ##STR45##               1642 cm.sup.-1                                        CC                       1602 cm.sup.-1                                        CH dif                    863 cm.sup.-1                                        ______________________________________                                    

EXAMPLE 20 N-[2-(dimethylamino)-ethyl]-3,17β-dihydroxy-N-methyl-11βΔ.sup.1,3,5(10) -estratriene undecanamide Step A N-[2-(dimethylamino)-ethyl]-3,17β-diacetyloxy-N-methyl-11β-.DELTA.¹,3,5(10) -estratriene undecanamide

Using the procedure of Step B of Example 3, 800 mg of the product of Step A of Example 19 were reacted to obtain after chromatography over silica (eluant: toluene-triethylamine (8-2)), 700 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                          Phenolic acetate                                                                             1767- 1750 cm.sup.-1                            C═O          Acetate at 17 1727 cm.sup.-1                                                   Tertiary amide                                                                               1630 cm.sup.-1                                                                 1587 cm.sup.-1                                  Aromatic                       1494 cm.sup.-1                                  Bohlmann band                                                                  ______________________________________                                    

Step B N-[2-(dimethylamino-ethyl]-3,17β-dihydroxy-N-methyl 11β-Δ¹,3,5(10) -estratriene undecanamide

Using the procedure of Step B of Example 10, 800 mg of the product of Step A were reacted to obtain after chromatography over silica (eluant: toluene-triethylamine (8-2)), 550 mg of product which was chromatographed once more (eluant: ethyl acetate-isopropanol-ammonia (80-2-2)) to obtain 527 mg of the desired product with a specific rotation of [α]_(D) =+77.5°±1.5° (c=0.9% in EtOH).

    ______________________________________                                         Analysis: C.sub.34 H.sub.56 O.sub.3 N.sub.2 ; molecular weight = 540.80        Calculated:                                                                               % C    75.51    % H  10.44 % N  5.18                                Found:            75.3          10.6       5.2                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                             OH            3607 cm.sup.-1                                                   Amide III     1627 cm.sup.-1                                                                 1582 cm.sup.-1                                                   Aromatics     1498 cm.sup.-1                                            ______________________________________                                    

EXAMPLE 21 N-butyl-3,17β-dihydroxy-N-methyl-19-nor-11β-Δ¹,3,5(10) -pregnatrien-20-yne-undecanamide Step A N-butyl-3,17-dioxo-N-methyl-11β-Δ⁴,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 7.5 g of the acid of Step B of Preparation 6 and 6.4 ml of N-methyl butylamine were reacted to obtain 5.89 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Tertiary amide        1628 cm.sup.-1                                           ______________________________________                                    

Step B 3-acetyloxy-N-butyl-N-methyl-17-oxo-11β-Δ¹,3,5(10) -estratriene undecanamide

Using the procedure of Step B of Example 3, 2.63 g of the product of Step A were reacted to obtain 2.91 g of crude product which was used as is in the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O       1735 cm.sup.-1 (17 keto + phenolic OAc)                          Tertiary amide                                                                               1627 cm.sup.-1                                                   Aromatic      1494 cm.sup.-1                                                   ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-N-methyl-19-nor-11β-Δ¹,3,5(10) -pregnatrien-20-yn undecanamide

To a solution of 1 g of the product of Step B in 10 ml of ethylenediamine, 1.62 g of lithium acetylide-ethylenediamine complex was added and the mixture was stirred for 4 hours 30 minutes at 50° C., then cooled. 20 g of ice, 10 ml of a saturated solution of ammonium chloride and 30 ml of methylene chloride were added and the mixture was filtered. The aqueous phase was re-extracted with methylene chloride and the combined organic phases were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure, The 0.805 g of residue was chromatographed over silica (eluant: methylene chloride-acetone (9-1)) to obtain 0.58 g of product which was chromatographed again over silica (eluant: methylene chloride-acetone (95-5)) to obtain 0.489 g of the desired product with a specific rotation of [α]_(D) =+40.5°±2.5° (c=0.5% in EtOH).

    ______________________________________                                         Analysis: C.sub.36 H.sub.55 O.sub.3 N; molecular weight = 549.80               Calculated:                                                                               % C    78.64    % H  10.08 % N  2.54                                Found:            78.3          10.4       2.4                                 ______________________________________                                         IR Spectrum: CHCl.sub.3 (on Nicolet)                                           Absence of 17 keto                                                             OH                3599 cm.sup.-1 + associated                                  C═CH          3304 cm.sup.-1                                               Amide             1620 cm.sup.-1                                                                 1582 cm.sup.-1                                               Aromatic          1490 cm.sup.-1                                               ______________________________________                                    

EXAMPLE 22 N-butyl-17β-hydroxy-3-oxo-17α-(1-propynyl1)-11β-Δ.sup.4,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 1.37 g of the product of Preparation 7 and 1.4 ml of butylamine were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl acetate (5-5)), 744 mg of the desired product.

    ______________________________________                                         Analysis: C.sub.35 H.sub.55 NO.sub.3 ; molecular weight                        ______________________________________                                         = 549.844                                                                      Calculated: % C 78.64 % H 10.08  % N 2.55                                      (Solvate with 2%                                                                           78.15     10.46      2.49                                          ethyl acetate)                                                                 Found:      78.2      10.4       2.4                                           ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                          ##STR46##       3450 cm.sup.-1                                                Amide II         1519 cm.sup.-1                                                CO               1657 cm.sup.-1 + conjugated ketone                            ______________________________________                                    

EXAMPLE 23 N-butyl-17β-hydroxy-N-methyl-3-oxo-17α-(1-propynyl)-11β-.DELTA.⁴,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 962 mg of the acid of Preparation 7 and 1 ml of N-methyl butylamine were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl acetate (5-5)), 0.79 g of the desired product.

    ______________________________________                                         Analysis: C.sub.37 H.sub.57 NO.sub.3 ; molecular weight = 563.87               Calculated:                                                                               % C    78.81    % H  10.19 % N  2.48                                Found:            78.5          10.5       2.3                                 ______________________________________                                         IR Spectrum; (CHCl.sub.3)                                                      Tertiary amide    1630 cm.sup.-1                                               OH                3602 cm.sup.-1                                               Conjugated ketone 1643 cm.sup.-1 with amide III                                ______________________________________                                    

EXAMPLE 24 N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene dodecanamide Step A N-butyl-N-methyl-3,17-dioxo-11β-Δ⁴,9 -estradiene dodecanamide

Using the procedure of Step A of Example 1, 1 g of the alcohol of Step B of Preparation 8 and 1.1 ml of N-methyl-butylamine were reacted to obtain after chromatography over silica (eluant: ethyl acetate-cyclohexane (8-2)), 717 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Little or no OH                                                                C═O (17 keto)                 1735 cm.sup.-1                                                  Conjugated ketone                                                                             1655 cm.sup.-1                               C═O                           1643 cm.sup.-1                                                  Tertiary amide 1628 cm.sup.-1                               --C═C          (ep.)          1603 cm.sup.-1                               ______________________________________                                    

Step B N-butyl-N-methyl-17β-hydroxy-11β-Δ⁴,9 -estradiene dodecanamide

To a solution of 837 mg of the product of Step A in 17 ml of tetrahydrofuran at 0° C., 494 mg of aluminium lithium tri-terbutoxy hydride were added for 20 minutes at 0° C. 20 ml of a saturated solution of ammonium chloride were added and the mixture was extracted with ethyl acetate and with methylene chloride. The organic phase was evaporated to dryness under mixture was extracted with ethyl acetate and with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 836 mg of residue were chromatographed over silica (eluant: ethyl acetate-cyclohexane (6-4)) to obtain 604 mg of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH      3612 cm.sup.-1                                                          C═O                                                                                1642 cm.sup.-1 (ep.)                                                                              Possibly encompassing                              Complex 1628 cm.sup.-1 (max)                                                                              dienone + tertiary amide                            Intense                                                                        aliphatics                                                                     ______________________________________                                    

Step C N-butyl-3,17β-dihydroxy-N-methyl-11β-Δ¹,3,5(10) -estratriene dodecanamide

To a solution cooled to 0° C. of 0.2 g of the product of Step B in 2.6 ml of methylene chloride, 0.26 ml of acetic anhydride and 0.13 ml of acetyl bromide were added at 0° C. and was allowed to recover to ambient temperature. After 1 hour, 20 ml of sodium bicarbonate in saturated solution were added and the mixture was stirred for 30 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 250 mg of residue were taken up in 10 ml of methanol. 150 mg of potassium hydroxide pellets were added to the solution which was heated for 2 hours at 40° C., then cooled to 0° C. The mixture was neutralized with concentrated hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 188 mg of residue were chromatographed over silica (eluant: cyclohexane-ethyl acetate (6-4)) to obtain 131 mg of the expected product with a specific rotation of [α]_(D) =+89°±3° (c=0.6% in EtOH).

    ______________________________________                                         Analysis: C.sub.35 H.sub.57 NO.sub.3                                           Calculated:                                                                               % C    77.87    % H  10.64 % N  2.59                                Found:            77.8          10.5       2.5                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3606 cm.sup.-1 + associated                                   C═O          1620 cm.sup.-1                                                Aromatic         1582 cm.sup.-1                                                                 1498 cm.sup.-1                                                ______________________________________                                    

EXAMPLE 25 1-[11-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-1-oxo-undecyl]-pyrrolidine Step A 1-[11-(17β-acetyloxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-1-oxo-undecyl]-pyrrolidine

Using the procedure of Step A of Example 3, 2.76 g of the acid of Step E of Preparation 5 and 2.5 ml of pyrrolidine were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl acetate (4-6)), 2.18 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Little or no acid                                                                                  1728 cm.sup.-1 OAC                                         C═O             1650 cm.sup.-1 Dienone +                                                       1622 cm.sup.-1 tertiary amide                              ______________________________________                                    

Step B 1-[11-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-1-oxo-undecyl]-pyrrolidine

For 40 minutes, a solution of 1.265 g of the product of Step A in 10 ml of N ethanolic potassium hydroxide was stirred and 12 ml of N hydrochloric acid and then 2 ml of concentrated ammonia were added. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The 1.164 g of residue were chromatographed over silica (eluant: ethyl acetate-cyclohexane (8-2)) to obtain 988 mg of the desired product.

    ______________________________________                                         Analysis: C.sub.33 H.sub.51 O.sub.3 N; molecular weight = 509.78               Calculated:                                                                               % C    77.75    % H  10.08 % N  2.74                                Found:            77.4          10.4       2.7                                 ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH + associated       3614 cm.sup.-1                                           C═O conjugated    1643 cm.sup.-1                                           Tertiary amide        1623 cm.sup.-1                                           ______________________________________                                    

EXAMPLE 26 1-[11-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-1-oxo-undecyl]-pyrrolidine

773 mg of the product of Step A of Example 25 dissolved in 8 ml of methylene chloride at 0° C. to +5° C. were admixed with 0.4 ml of acetyl bromide and 0.8 ml of acetic anhydride and the mixture was stirred for 2 hours while allowing the temperature rise to ambient temperature. After adding ice and neutralizing by addition of sodium bicarbonate, the mixture was washed with water, dried and evaporated to dryness under vacuum to obtain 829 mg of the intermediate diacetate.

The 829 mg of product were reacted as in Step B of Example 25 and after chromatography over silica (eluant: ethyl acetate alone, then ethyl acetate with 20% methanol); 545 mg of the expected crude product were obtained which were crystallized from a methylene chloride-isopropyl ether mixture, then from ethyl acetate to obtain 396 mg of the desired product melting at 150° C. and having a specific rotation of [α]_(D) =+70°±2.5° (c=0.5% in CHCl₃).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH free + associated   3607 cm.sup.-1                                          C═O                1617 cm.sup.-1                                          Aromatics              1582 cm.sup.-1                                                                 1498 cm.sup.-1                                          ______________________________________                                    

PREPARATION OF EXAMPLE 27 11β-[4-(8-hydroxyoctyl)-phenyl]-Δ⁴,9 -estradien-3,17-dione

Using the procedure of Step A of preparation 6, 8.5 g of the product of Step A of preparation 4 were reacted to obtain after chromatography on silica (elution with methylene chlorideacetone 9-1), 5.65 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         --OH                   3623 cm.sup.-1                                          17 keto                1733 cm.sup.-1                                          non conjugated ketone  1712 cm.sup.-1                                          aromatic               1605 cm.sup.-1                                                                 1506 cm.sup.-1                                          ______________________________________                                    

EXAMPLE 27 4-[3-hydroxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl-N-methyl-N-isoproply-benzene]-octanamide Step A 4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-N-methyl-N-isopropyl-benzene octanamide

Using the procedure of Example 1, 7.05 g of the product of preparation 14 and 7.9 ml of N-methyl-isopropylamine for the amidification were reacted, and after chromatography on silica (eluant: methylene chloride-acetone 9-1) obtained 5.99 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                amide III     1621 cm.sup.-1                                                   17-keto       1735 cm.sup.-1                                                   dienone       1657 cm.sup.-1                                                   Aromatics     1510 cm.sup.-1                                            ______________________________________                                    

Step B 4-(3-acetyloxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl)-N-methyl-N-isopropyl-benzene octanamide

Using the procedure of Step B of Example 3, 4 g of the product of Step A and 1.9 ml of acetyl bromide and 3.8 ml of acetic anhydride were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 4.2 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of dienone                                                             Phenolic acetate          1755 cm.sup.-1 (ep.)                                 17-keto                   1731 cm.sup.-1                                       amide III                 1621 cm.sup.-1                                                                  1513 cm.sup.-1                                      Aromatic                                                                                                 1493 cm.sup.-1                                       ______________________________________                                    

Step C 4-(3-hydroxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl)-N-methyl-N-isopropyl-benzene octanamide

Using the procedure of Example 2, 2.3 g of the product of Step B were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1) 2 g of the desired product with a specific rotation of [α]_(D) =-16°±2° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                       3600 cm.sup.-1                                        17-keto                  1732 cm.sup.-1                                        amide III                1617 cm.sup.-1                                                                 1583 cm.sup.-1                                        Aromatics                1510 cm.sup.-1                                                                 1501 cm.sup.-1                                        ______________________________________                                    

EXAMPLE 28 4-[3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-N-methyl-N-isopropyl-benzene octanamide

To a solution of 480 mg of the product of Example 27 and 7.5 ml of anhydrous tetrahydrofuran, there were added at 0° C./+5° C. 563 mg of triterbutoxy lithium aluminium hydride. The mixture was stirred for 50 minutes and 100 mg of the hydride were added. The solution was poured into a 1-1 mixture of ice and of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried, filtered and evaporated to dryness. After chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 472 mg of desired product with a specific rotation of [α]_(D) =-34.5°±2.5° (c=0.5% in ethanol) were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                        3605 cm.sup.-1                                       amide III                 1617 cm.sup.-1                                                                  1583 cm.sup.-1                                      Aromatics                                                                                                1499 cm.sup.-1                                       ______________________________________                                    

EXAMPLE 29 4-[3,17β-dihydroxy-19-nor-17α-Δ¹,3,5(10) -pregnatrien-20-yn-11β-yl]-N-methyl-N-isopropyl benzene octanamide

To a solution of 400 mg of the product of Example 27 in 20 ml of tetrahydrofuran, there were added over 3 hours 30 minutes 825 mg of lithium ethylene diamine acetylide and the mixture was stirred for 4 hours and poured into a 1-1 mixture of ice and a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate, washed with water saturated with sodium chloride, dried, filtered and evaporated to dryness. The residue was chromatographed on silica twice, each time using eluant: methylene chloride-acetone 93-7, to obtain 115 mg of the desired product with a specific rotation of [α]_(D) =-105°±2° (c=0.9% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                        3599 cm.sup.-1                                       C.tbd.CH                  3304 cm.sup.-1                                       amide III                 1617 cm.sup.-1                                                                  1583 cm.sup.-1                                      Aromatics                                                                                                1500 cm.sup.-1                                       ______________________________________                                    

EXAMPLE 30 4-[3,17β-dihydroxy-17α-methyl-Δ¹,3,5(10) -estratrien-11β-yl]-N-methyl-N-isopropyl benzene octanamide

To a solution of 700 mg of the product of Example 27 in 35 ml of tetrahydrofuran, there were added at 20°/25° C. 12.8 ml of a 0.76M solution of methyl magnesium bromide in tetrahydrofuran. After one hour of reaction, the solution was poured into a 1-1 mixture of ice and of a saturated solution of ammonium chloride and was extracted with ethyl acetate. The extracts were washed with a saturated solution of sodium chloride, dried, filtered and evaporated to dryness. The residue was chromatographed on silica (eluant: methylene chloride-acetone 9-1) to obtain 411 mg of the desired product.

    ______________________________________                                         Analysis: C.sub.37 H.sub.53 NO.sub.3 ; molecular weight                        ______________________________________                                         = 559.84                                                                       Calculated:                                                                               % C    79.38    % H  9.54  % N  2.50                                Found:            79.4          9.5        2.4                                 ______________________________________                                    

PREPARATION A OF EXAMPLE 31 4-trimethylsilylethynyl bromo benzene

A mixture of 150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis-(triphenylphosphine)-palladium (II) dichloride was stirred for 2 hours and then 500 ml of ice-cooled water were added. The mixture was extracted 3 times with 500 ml of ethyl acetate and the organic phase was washed with salt water, then dried over sodium sulfate, and evaporated under reduced pressure to obtain 136.542 g of a brown oil which was purified by distillation under reduced pressure to obtain 106.979 g of the expected product with a boiling point of 75°-82° C. under 0.2 mbar and a melting point of 62° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of C.tbd.CH                                                            C═C               2160 cm.sup.-1                                           ______________________________________                                    

PREPARATION B OF EXAMPLE 31 Step A 3-(1,2-ethanediyl cyclic acetal)-5α-hydroxy-11β-[[4-(1,1-dimethylethyl)-dimethylsilyl]-ethynyl-phenyl]-Δ⁹ -estren 3,17-dione

Using the procedure of Step A of preparation 1, 30 g of 3-(1,2-ethanediyl cyclic acetal) of 5α,10α-epoxy-Δ⁹ -estren-3,17-dione of EP Patent No. 0,057,115 (Example 7) using, for the preparation of the magnesium compound, 81.254 g of the brominated derivative of preparation A, and 7.96 g of magnesium, then for the condensation, 1.4 g of copper chloride were reacted and after chromatography on silica, the crude product obtained and the product of an operation carried out in the same way starting with 16.52 g of epoxide (eluant: methylene chloride-acetone 98-2) were reacted to obtain 50.8 g of pure product A and 6 g of slightly less pure product B which were used as they are for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                        3508 cm.sup.-1                                       C═C                   2156 cm.sup.-1                                                                 1602 cm.sup.-1                                       Aromatics                 1555 cm.sup.-1                                                                 1502 cm.sup.-1                                       ______________________________________                                    

Step B 11β-(4-ethynylphenyl)-Δ⁴,9 -estradien-3,17-dione

A suspension of 46.8 g of the product of Step A, 200 ml of ethanol and 8.1 ml of sodium hydroxide was stirred for 30 minutes and 16.7 ml of concentrated hydrochloric acid were added. The mixture was stirred at ambient temperature and then concentrated to half the volume and extracted with methylene chloride. The organic phase was dried and evaporated under reduced pressure. The 38.23 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 31.06 g of the desired product melting at 184° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.CH               3302 cm.sup.-1                                          C═O                1736 cm.sup.-1 (17-keto)                                                       1659 cm.sup.-1                                                                 1640 cm.sup.-1 dienone                                  Aromatic               1556, 1506 cm.sup.-1                                    ______________________________________                                    

Step C 3β-hydroxy-11β-(4-ethynyl phenyl)-Δ¹,3,5(10) -estratrien-17-one Acetylation at Position 3

Using the procedure of Step B of Example 3, 31 g of the compound of Step B and 47.1 ml of acetic anhydride and 23.8 ml of acetyl bromide were reacted to obtain 31.2 g of 3-acetate which was saponified by using the procedure of Step B of Example 1. After chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), 27.03 g of crude product were obtained and made into a paste in ether to collect 22.852 g of the desired product melting at 163° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH             3597 cm.sup.-1                                                  C.tbd.CH       3303 cm.sup.-1                                                  C═O        1733 cm.sup.-1                                                  Aromatic       1606, 1582, 1556, 1503 cm.sup.-1                                ______________________________________                                    

Step D 3,17β-tetrahydropyrannyloxy-11β-(4-ethynylphenyl)-Δ¹,3,5(10) -estratriene a) Reduction of the 17-ketone

Using the procedure of Step B of Example 3, 14 g of the compound of Step C and 10 g of sodium borohydride were reacted.

b) Dihydropyranylation

Using the procedure of Step A of Example 39, 17.3 g of the 17-hydroxy intermediate obtained above and 24.4 ml of dihydropyran and 0.3 g of p-toluene sulfonic acid were reacted to obtain after chromatography on silica, 13.6 g of crude product which was taken up in isopropyl ether to collect 10.23 g of the desired product melting at 213° to 215° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.CH       3302 cm.sup.-1                                                  Aromatic       1607, 1570, 1556, 1498 cm.sup.-1                                ______________________________________                                    

PREPARATION C OF EXAMPLE 31 1-oxo-6-bromo hexyl morpholine

Using the procedure of Step A of Example 3, 5 g of 6-bromo-benzylic acid and 3.4 ml of N-methyl morpholine, 3.7 ml of isobutyl chloroformate and 3.35 ml of morpholine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 9-1), 7 g of the desired product which was used as is for the following step.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         CO                   1635 cm.sup.-1                                             ##STR47##           1115 cm.sup.-1                                            ______________________________________                                    

EXAMPLE 31 4-(8-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl-1-oxo-7-octynyl)-morpholine

To a solution cooled to -30° C. of 800 mg of the compound of Preparation B of Example 31 in 6.5 ml of tetrahydrofuran and 6.5 ml of hexamethylphosphotriamide, 1.7 ml of a 1.1M solution of butyllithium in hexane were added dropwise and after stirring for 5 minutes at -30° C., 508 mg of 1-oxo-6-bromo hexyl morpholine of Preparation C above in solution in 1 ml of tetrahydrofuran at -25° to -30° C. were added. The mixture was stirred for one hour and poured into 30 ml of a sodium chloride solution. The mixture was extracted with ethyl acetate and the extracts were washed, dried and evaporated to dryness under reduced pressure and the 3 g of crude product were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 760 mg of the product which was depyranylised for one hour at ambient temperature with a mixture of 8 ml of 2N hydrochloric acid and 40 ml of methanol. The mixture was poured into 50 g of water and ice (1-1), extracted with methylene chloride, and evaporated to dryness under reduced pressure. The 665 mg of residue were chromatographed on silica (eluant: methylene chloride-acetone 8-2) to obtain 502 mg of the desired product which after crystallization from ether had a specific rotation of [α ]_(D) =-36.5°±2.5° (c=1% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3603 cm.sup.-1                                                C═O          1631 cm.sup.-1                                                Aromatic         1584, 1550, 1505 cm.sup.-1                                    Morpholine       1115 cm.sup.-1                                                ______________________________________                                         Analysis:                                                                               C.sub.36 H.sub.45 NO.sub.4 ; molecular weight = 555.76                Calculated:                                                                             % C     77.80   % H   8.16  % N   2.52                                Found:           77.8          8.3         2.5                                 ______________________________________                                    

EXAMPLE 32 4-[8-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl]-1-oxo octyl)-morpholine

To a solution of 290 mg of the product of Example 31 in 15 ml of ethanol, there were added 145 mg of palladium on 10% activated carbon, and hydrogenation was effected under 1300 mbar. The mixture was filtered and the filtrate was evaporated to dryness. The 280 mg of residue were chromatographed on silica (eluant: methylene chloride-acetone 85-15) and taken up in ether to obtain 256 mg of the desired product with a specific rotation of [α]_(D) =-30°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3604 cm.sup.-1                                                C═O          1629 cm.sup.-1                                                Aromatic         1583, 1500 cm.sup.-1                                          Morpholine       1115 cm.sup.-1                                                ______________________________________                                         Analysis:                                                                               C.sub.36 H.sub.49 NO.sub.4 ; molecular weight = 559.8                 Calculated:                                                                             % C     77.24   % H   8.82  % N   2.56                                Found:           77.5          9.1         2.5                                 ______________________________________                                    

PREPARATION OF EXAMPLE 33 N-dibutyl-6-bromohexanamide

Using the procedure of Step A of Example 3, 4.41 g of 5-bromohexanoic acid and 11.1 g of dibutylamine were reacted to obtain the desired product which after distillation under reduced pressure resulted in 6.141 g of the expected product with a boiling point of 139° C. under 0.5 mbar.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O    1623 cm.sup.-1 (amide III)                                          ______________________________________                                    

EXAMPLE 33 8-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl)-N,N-dibutyl-7-octynamide

Using the procedure of Example 31, 0.7 of the compound of Preparation 33 and 0.463 mg of bromo-dibutyl-7-octynamide (Preparation of Example 33) were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 657 mg of the expected product with a specific rotation of [α]_(D) =-26°±2° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                OH     3603 cm.sup.-1                                                          C═O                                                                               1621 cm.sup.-1                                                          Aromatic                                                                              1582 cm.sup.-1                                                   ______________________________________                                         Analysis:                                                                               C.sub.40 H.sub.55 NO.sub.3 ; molecular weight = 597.89                Calculated:                                                                             % C     79.82   % H    9.88 % N   2.33                                Found:           79.7          10.1        2.4                                 ______________________________________                                    

EXAMPLE 34 8-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl)-N,N-dibutyl-7-octanamide

Using the procedure of Example 32, 381 mg of the product of Example 33 and 0.1 g of palladium on activated carbon were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 241 mg of the desired product with a specific rotation of [α]_(D) =-26°±2° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3605 cm.sup.-1                                              C═O            1619 cm.sup.-1                                              Aromatic           1583, 1500 cm.sup.-1                                        ______________________________________                                         Analysis:                                                                               C.sub.40 H.sub.59 NO.sub.3 ; molecular weight = 602.92                Calculated:                                                                             % C     79.82   % H    9.88 % N   2.33                                Found:           79.7          10.1        2.4                                 ______________________________________                                    

PREPARATION OF EXAMPLE 35 N-methyl-N-butyl-1-iodo-hexanamide

To a solution of 5.288 g of N-methyl-N-butyl-1-bromo hexanamide (Preparation of Example 33) in 105 ml of acetone, there were added 4.497 g of sodium iodide and the mixture was stirred for 18 hours, then filtered and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness under vacuum to obtain 6.139 g of the expected product.

EXAMPLE 35 8-(4-3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl)-N-butyl-N-methyl-7-octynamide

Using the procedure of example 33, 692 mg of the product of Preparation 33 and 516 mg of N-methyl-N-butyl-1-iodo-hexanamide (Preparation of Example 35) were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 2-8) to obtain 586 mg of the expected product with a specific rotation of [α]_(D) =-35.5°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                   3605 cm.sup.-1                                            C═O              1621 cm.sup.-1                                            C═C + Aromatic   1583, 1500 cm.sup.-1                                      ______________________________________                                         Analysis:                                                                               C.sub.37 H.sub.49 NO.sub.3 ; molecular weight = 557.81                Calculated:                                                                             % C     79.95   % H   8.88  % N   2.51                                Found:           79.8          9.0         2.5                                 ______________________________________                                    

EXAMPLE 36 (Z) 8-(4-(3,17β-dihydroxy-Δ1,3,5(10)-estratrien-11β-yl)-phenyl-N-methyl-7-octenamide

To a solution of 555 mg of the product of Example 35 in 11 ml of ethyl acetate, 50 mg of palladium on barium sulfate and 0.22 ml of pyridine were added and hydrogenation was effected under a pressure of 1500 mbars. The mixture was filtered and evaporated to dryness under reduced pressure to obtain 620 mg of residue which was chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 360 mg of the desired product which was chromatographed a second time under these conditions to obtain 344 mg of the pure compound with a specific rotation of [α]_(D) =-32°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         --OH                 3605 cm.sup.-1                                            C═O              1621 cm.sup.-1                                            C═C + Aromatic   1583, 1500 cm.sup.-1                                      ______________________________________                                         Analysis:                                                                               C.sub.37 H.sub.51 NO.sub.3 ; molecular weight = 557.82                Calculated:                                                                             % C     79.66   % H   9.21  % N   2.5                                 Found:           79.5          9.4         2.4                                 ______________________________________                                    

EXAMPLE 37 2-((7-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl-6-heptynyl)-oxy)-N-butyl-N-methyl acetamide

Using the procedure of Example 33, 0.7 g of the compound of Preparation B of Example 31 and 0.493 g of [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide (Preparation 21) were reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclohexane 8-2), 460 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH              3603 cm.sup.-1 + associated                                    C═O         1634 cm.sup.-1                                                 Aromatic        1584, 1554, 1505 cm.sup.-1                                     ______________________________________                                         Analysis:                                                                               C.sub.38 H.sub.51 NO.sub.4 ; molecular weight = 585.829               Calculated:                                                                             % C     77.91   % H   8.78  % N   2.39                                Found:           78.2          8.9         2.5                                 ______________________________________                                    

EXAMPLE 38 2-((7-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl)-heptyl)-oxy)-N-butyl-N-methyl acetamide

Using the procedure of Example 34, 300 mg of the product of Example 37 and 0.1 g of palladium on activated carbon were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 201 mg of the desired product with a specific rotation of [α]_(D) =-19°±1° (c=1% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         --OH               3604 cm.sup.-1                                              C═O            1635 cm.sup.-1                                              Aromatic           1583, 1500 cm.sup.-1                                        ______________________________________                                         Analysis:                                                                               C.sub.38 H.sub.55 NO.sub.4                                            Calculated:                                                                             % C     77.38   % H   9.40  % N   2.37                                Found:           77.2          9.7         2.4                                 ______________________________________                                    

EXAMPLE 39 N-butyl-4-[3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-α,α-N-trimethyl benzene octanamide Step A N-butyl-N-methyl-4-[3,17β-bis-[(tetrahydro-2H-pyran-2-yl)-oxy]-Δ¹,3,5(10) -estratrien-11β-yl]-benzene octanamide

A mixture of 500 mg of the product of Example 8, 20 ml of ether, 15 ml of dihydropyran and 15 mg of p-toluene sulfonic acid was stirred for 150 minutes and then 1 ml of triethylamine was added. The mixture was poured into a 1-1 mixture of ice and saturated solution of sodium bicarbonate and extracted with ether. The organic phase was filtered and evaporated to dryness and the residue was chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 640 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Absence of OH, presence of tetrahydropyranyl ether                             ______________________________________                                         amide III                 1627 cm.sup.-1                                                                 1574 cm.sup.-1                                       Aromatics                 1510 cm.sup.-1                                                                 1497 cm.sup.-1                                       ______________________________________                                    

Step B N-butyl-α-N-dimethyl-4-[3,17β-bis-[(tetrahydro-2H-pyran-2-yl)-oxy-Δ¹,3,5(10) -estratrien-11β-yl]-benzene octanamide

To a solution of 0.7 ml of diisopropylamine in 5 ml of anhydrous tetrahydrofuran, there were added at 5° to 8° C. 2.8 ml of a 1.6M solution of butyllithium in hexane and the mixture was stirred for 10 minutes at +5° C., then cooled to -70° C. and a solution of 630 mg of the product of Step A in 5 ml of anhydrous tetrahydrofuran was added. The mixture was stirred for 30 minutes at -70° C. and after 0.5 ml of methyl iodide were added, the mixture was stirred for 45 minutes. 20 ml of a saturated solution of ammonium chloride were added and the mixture returned to ambient temperature. The mixture was extracted with ethyl acetate, and the organic phase was washed, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: cyclohexane-ethyl acetate 8-2) to obtain 567 mg of the desired product which was used as is for the following step.

NMR Spectrum 300 MHz: -methyl of the amine: 1.07 (d) and 1.08 (d).

Step C N-butyl-4-[3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-α,α-N-trimethyl benzene octanamide a) Dimethylation

To a solution of 516 mg of the product of Step B in 11.5 ml of tetrahydrofuran, there were added at 48° C.±2° C. 9 ml of a solution of lithium diisopropylamide (prepared at +5°/+8° C. by addition of 6.2 ml of a 1.6M solution of butyllithium in hexane to a solution of 1.4 ml of diisopropylamine in 10 ml of tetrahydrofuran). Once the addition of the lithium diisopropylamine was complete, the mixture was stirred for 15 minutes and 1.2 ml of methyl iodide were added in one lot. The resulting medium was stirred for 45 minutes and then poured into 50 g of a 1-1 mixture of ice and saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness to obtain 560 mg of intermediate N-butyl-α,α-N-trimethyl-4-[3,17β-bis-(tetrahydro-2H-pyran-2-yl)-oxy]-Δ¹,3,5(10) -estratrien-11β-yl]-benzene octanamide which was used as is for the depyranylation.

b) Depyranylation

The dry extract obtained above was dissolved in 15 ml of methanol and 2 ml of 2N hydrochloride acid were added. The mixture was stirred for one hour at ambient temperature and poured into a saturated solution of sodium chloride. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness, and the 465 mg of residue were chromatographed on silica (eluant:methylene chloride-acetone 95-5) to obtain after trituration in ether, 207 mg of the desired product with a specific rotation of [α]_(D) =-30° C.±2.5° (c=0.5% in ethanol).

    ______________________________________                                         Analysis:                                                                               C.sub.39 H.sub.57 NO.sub.3 ; molecular weight = 587.85                Calculated:                                                                             % C     79.68   % H   9.77  % N   2.38                                Found:           79.8          9.9         2.5                                 ______________________________________                                    

PREPARATION OF EXAMPLE 40 4-(3,7-dioxo-Δ⁴,9 -estradien-11β-yl)-benzene octanol

Using the procedure of Preparation 6A, 3.6 g of the product of Preparation 4A were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 95-5), 2.234 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3623 cm.sup.-1                                                C═O          1735 cm.sup.-1                                                Dienone          1658, 1602 cm.sup.-1                                          Aromatic         1570 (ep.), 1510 cm.sup.-1                                    ______________________________________                                    

EXAMPLE 40 4-[3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-N-methyl-N-isopropyl benzene nonamide Step A 4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-benzene octane methane sulfonate

To a solution of 2.234 g of the product of the Preparation of Example 40 in 20 ml of anhydrous pyridine, there were added 3.36 g of p-toluene sulfonyl chloride and the mixture was stirred for 80 minutes. 30 ml of a saturated solution of sodium bicarbonate were added and the mixture was stirred for 30 minutes and extracted with methylene chloride. The solvents were dried, then evaporated to dryness under reduced pressure. The 2.9 g of residue were chromatographed on silica (eluant: methylene chloride-acetone 9-1) to obtain 2.255 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O (17-keto) 1735 cm.sup.-1                                               Dienone           1658, 1600 cm.sup.-1                                         Aromatic          1510, 1496 cm.sup.-1                                         SO.sub.2          1359, 1496, 1176 cm.sup.-1                                   ______________________________________                                    

Step B 4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-benzene nonane iodide

2.2 g of the product of Step A in 50 ml of acetone and 0.787 g of sodium iodide were stirred at reflux for one hour and then filtered. The filtrate was evaporated to dryness under reduced pressure and the 3.6 g of residue were taken up in 10 ml of ether and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 1.722 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O            1735 cm.sup.-1                                              Dienone            1658, 1602 cm.sup.-1                                        Aromatic           1510 cm.sup.-1                                              ______________________________________                                    

Step C 4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-benzene decane nitrile

3.6 g of the product of Step B in 55 ml of ethanol and 10 ml of water with 0.872 g of potassium cyanide were stirred at refux for 2 hours and then 50 ml of ice were added. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated under reduced pressure to obtain 1.68 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.N            2245 cm.sup.-1                                              C═O            1735 cm.sup.-1                                              Dienone            1658, 1602 cm.sup.-1                                        Aromatic           1500 cm.sup.-1                                              ______________________________________                                    

Step D 4-(3-acetoxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl)-benzene decane nitrile

Using the procedure of Step B of Example 3, 1.27 g of the product of Step C were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 1.281 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.N             2245 cm.sup.-1                                              C═O             1750 cm.sup.-1 (OAC)                                                          1735 cm.sup.-1 (17-keto)                                   Aromatic            1606, 1582, 1512, 1413 cm.sup.-1                           ______________________________________                                    

Step E 4-(3-isobutyl-carbonyloxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl)-N-methyl-N-isopropyl-benzene nonamide a) Hydrolysis of the nitrile

1.225 g of the product of Step D, 24 ml of ethanol and 1.5 ml of sodium hydroxide were stirred at reflux for 60 hours and then cooled and poured into a mixture of 73 ml of N hydrochloric acid and 100 ml of ice. The mixture was stirred for 10 minutes and extracted with methylene chloride. The organic phase was dried, filtered and concentrated to dryness under reduced pressure to obtain 1.145 g of the desired product.

b) Amidification

To a solution of 1.145 g of the said product in 50 ml of methylene chloride, there were added 0.3 ml of N-methyl morpholine and 1 ml of isobutyl chloroformate and the mixture was stirred for 10 minutes. 1 ml of isopropyl methylamine was added and the mixture was stirred for 30 minutes at ambient temperature and then poured into 50 ml of a saturated solution of sodium bicarbonate. The mixtue was stirred for 10 minutes and then extracted with methylene chloride. The organic phase was dried and evaporated to dryness under reduced pressure. The 2 g of residue were chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) to obtain 0.778 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O                1755 cm.sup.-1 (ep.)                                                           1737 cm.sup.-1 (max)                                                           1621 cm.sup.-1 (amide III)                              Aromatic               1513, 1493 cm.sup.-1                                    ______________________________________                                    

Step F 4-[3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-N-methyl-N-isopropyl-benzene nonamide a) Reduction of the 17-keto

Into a solution of 0.778 g of the product of Step E in 15 ml of tetrahydrofuran, there were introduced by fractions 0.451 g of tritertbutoxy aluminium-lithium hydride. The mixture was stirred for 30 minutes, then poured into ice-cooled solution of monosodium phosphate. The mixture was stirred for 30 minutes and then extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure to obtain 0.9 g of the 17-hydroxy product.

b) Saponification

Using the procedure of Example 2B, the product obtained above was reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclohexane 6-4), 613 mg of the expected product with a specific rotation of [α]_(D) =-17°±1° (c=1% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                    3604 cm.sup.-1                                           C═O               1618 cm.sup.-1                                            Aromatic              1583 cm.sup.-1                                                                1500 cm.sup.-1                                           ______________________________________                                         Analysis:                                                                               C.sub.37 H.sub.53 NO.sub.3 ; molecular weight = 559.84                Calculated:                                                                             % C     79.38   % H   9.54  % N   2.50                                Found:           79.3          9.7         2.5                                 ______________________________________                                    

PREPARATION OF EXAMPLE 41 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-((6-hydroxy-hexyl)-oxy-phenyl]-Δ⁹ -estren-3,17-dione Step A 3-(1,2-ethanediyl) cyclic acetal of 11β-(4-hydroxyphenyl)-5α-hydroxy-Δ⁹ -estren-3,17-dione a) Preparation of the Magnesium Compound

Using the procedure of Step A of Example 1, 7.1 g of magnesium turnings and 50 g of 4-trimethylsilyloxy-bromo-benzene were reacted to obtain an approximately 0.95M solution of magnesium compound in tetrahydrofuran.

b) Condensation

Using the procedure of Step A of Example 1, 10 g 3-(1,2-ethanediyl) cyclic acetal of 5α,10α-epoxy-Δ⁹ -estren-3,17-dione obtained by EP 0,057,115 (Example 7) and 110 ml of the magnesium compound solution were reacted to obtain 34.9 g of crude product.

c) Desilylation

The crude product was dissolved in 150 ml of tetrahydrofuran, and after 130 ml of a 1M solution of tetrabutylammonium fluoride were added, the mixture was stirred for 15 minutes at ambient temperature, then poured into water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 26.9 g of crude product which was triturated at 40° C. for 30 minutes in 100 ml of an ethyl acetate-methylene chloride mixture (1-1). The mixture was filtered to obtain 5.77 g of the desired product. By chromatography on silica of the mother liquors (eluant: ethyl acetate-methylene chloride 1-1), an additional 5.7 g of the desired product were obtained and the combined batches of product (11.47 g) were crystallized from ethanol to obtain 8 g of the expected product melting at 255° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH region        3464, 3280 cm.sup.-1                                          C═O          1720 cm.sup.-1                                                Aromatic         1613, 1592, 1511 cm.sup.-1                                    ______________________________________                                    

Step B 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-((6-hydroxy-hexyl)-oxy)-phenyl]-Δ⁹ -estren-3,17-dione

To a solution of 3.77 g of the product of Step A in 18 ml of acetone, 13.3 ml of 2N sodium hydroxide and then 3 ml of bromohexanol were added and the mixture was heated at 50° C. for 3 hours, then poured into a saturated solution of ammonium chloride. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The 7.7 g of residue were chromatographed on silica (eluant: methylene chloride-ethyl acetate 6-4 then 1-1) to obtain 4.11 g of the desired compound.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH-- (of the chain)                                                                               3620 cm.sup.-1                                              OH at position 5α                                                                           3509 cm.sup.-1                                              Aromatic           1609, 1578, 1509 cm.sup.-1                                  ______________________________________                                    

EXAMPLE 41 7-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy)-N-methyl-N-isopropyl-heptanamide Step A 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-[(6-[(4-methylphenyl)-sulfonyloxy)-hexyl]-oxy]-phenyl]-Δ⁹ -estren-3,17-dione

Using the procedure of Step A of Example 40, 4.08 g of the compound of the Preparation of Example 41 and 2.85 g of p-toluene sulfonyl chloride were reacted to obtain after chromatography on silica (eluant: methylene chloride-ethyl acetate 2-1), 4.19 g of the desired product which was used as is for the following step.

Step B 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-[(6-iodohexyl)-oxy]-phenyl]⁹ -estrene-3,17-dione

Using the procedure of Step B of Example 40, 4.19 g of the product of Step A and 1.39 g of sodium iodide were reacted to obtain 3.9 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH at position 5  3508 cm.sup.-1                                               17-keto           1733 cm.sup.-1                                               Aromatic          1609, 1575, 1508 cm.sup.-1                                   ______________________________________                                    

Step C [4-[3,3-(1,2-ethanediyl)-bis-oxy-5α-hydroxy-17-oxo-Δ⁹ -estren-11β-yl]-phenoxy]-heptane nitrile

Using the procedure of Step C of Example 40, 3.75 g of the compound of Step B and 780 mg of potassium cyanide were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 2.9 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH at position 5α                                                                          3510 cm.sup.-1                                               C.tbd.N           2248 cm.sup.-1                                               17-keto           1733 cm.sup.-1                                               Aromatic          1609, 1576, 1508 cm.sup.-1                                   ______________________________________                                    

Step D [4-(3,20-dioxo-Δ⁴,9 -estradien-11β-yl)-phenoxy]-heptane nitrile

A mixture of 2.46 g of the product of Step C, 13 ml of methanol and 4 ml of 2N hydrochloric acid was stirred for 2 hours at ambient temperature and after dilution with water, and extraction with methylene chloride, the organic phase was distilled under reduced pressure to obtain 2.2 g of crude product which was chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 1.875 g of the desired product melting at 176° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.N          2250 cm.sup.-1                                                17-keto          1735 cm.sup.-1                                                3-keto           1658 cm.sup.-1                                                C═C          1609 cm.sup.-1                                                Aromatic         1609, 1580, 1509 cm.sup.-1                                    ______________________________________                                    

Step E 7-[4-(3-acetoxy-17β-hydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-heptane nitrile a) Aromatization

Using the procedure of Step B of Example 3, 1.693 g of the product of Step D and 1.7 ml of acetic anhydride and 0.85 ml of acetyl bromide were reacted to obtain 2.15 g of the desired crude product.

b) Reduction of the Ketone at Position 17

Using the procedure of Step B of Preparation 1, 2.15 g of the product above and 280 mg of sodium borohydride were reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclohexane 40-60), 1.12 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH             3612 cm.sup.-1                                                  C.tbd.N        2250 cm.sup.-1                                                  C═O        1753 cm.sup.-1                                                  Aromatic       1610, 1580, 1512, 1494 cm.sup.-1                                ______________________________________                                    

Step F 7-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl]-phenoxy]-heptanoic acid

Using the procedure of Step B of Example 2, 900 mg of the product of Step E were reacted to obtain after chromatography on silica (eluant: essence G-acetone 65-35 with 1% of acetic acid, then acetone only), 779 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3602 cm.sup.-1                                                C═O          1731, 1709 cm.sup.-1                                          Aromatic         1610, 1581, 1512 cm.sup.-1                                    ______________________________________                                    

Step G 7-(4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy)-N-methyl-N-isopropyl-heptanamide

Using the procedure of Step A of Example 3, 400 mg of the product of Step F and 0.34 ml of isopropyl methylamine were reacted to obtain 511 mg of crude product (intermediate carbonate at position 3) which was saponified as in Step A of Example 2. After chromatography on silica (eluant: ethyl acetate then acetone with 1% of acetic acid) 336 mg of the desired product with a specific rotation of [α]_(D) =-39°±2° (c=0.7% in ethanol) were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                3604 cm.sup.-1                                               C═O           1619 cm.sup.-1 amide III                                     aromatic          1581, 1511 cm.sup.-1                                         ______________________________________                                         Analysis:                                                                               C.sub.35 H.sub.49 NO.sub.4 ; molecular weight = 547.79                Calculated:                                                                             % C     76.74   % H   9.01  % N   2.55                                Found:           77.0          9.0         2.6                                 ______________________________________                                    

EXAMPLE 42 N-butyl-4-[3,17β-dihydroxy-19-nor-17α-Δ¹,3,5(10) -pregnatrien-20-yn-11β-yl]-N-methyl benzene

Using the procedure of Example 21, the product of Step A of Preparation 4 was reacted to obtained 250 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.CH           3305 cm.sup.-1                                              OH                 3598 cm.sup.-1                                              C═O            1621 cm.sup.-1                                              Aromatic           1583, 1500 cm.sup.-1                                        ______________________________________                                         Analysis:                                                                               C.sub.39 H.sub.53 NO.sub.3 ; molecular weight = 583.86                Calculated:                                                                             % C     80.23   % H   9.15  % N   2.4                                 Found:           80.1          9.3         2.34                                ______________________________________                                    

PREPARATION OF EXAMPLE 43 11β-(4-hydroxyphenyl-Δ⁴,9 -estradien-3,17-dione

Using the procedure of Step B of Preparation 3, 1 g of the compound of Step A of the Preparation of Example 41 was reacted to obtain after chromatography on silica (eluant: methylene chloride-ethyl acetate 7-3), 703 mg of the sought product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3596 cm.sup.-1                                              C═O            1735 cm.sup.-1                                              C═O            1657 cm.sup.-1                                              Aromatic           1612, 1593, 1511 cm.sup.-1                                  ______________________________________                                    

PREPARATION B OF EXAMPLE 43 [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide Step A Bromo-N-butyl-N-methyl acetamide

To a solution cooled to -20° C. of 11.9 ml of bromoacetyl bromide in 180 ml of ether there were added 26 g of butylmethylamine in solution in 120 ml of ether and then the temperature returned to 20° C. The mixture was stirred for 30 minutes and diluted with water and extracted with ether. The ether phase was evaporated to dryness under reduced pressure and the 27.4 g of residue were distilled under reduced pressure (0.05 mbar) at 79°/83° C. to obtain 19.36 g of the desired product.

    ______________________________________                                         Analysis: C.sub.7 H.sub.14 BrNO; molecular weight = 208.105                    ______________________________________                                         Calculated:                                                                            % C    40.40  % H  6.78 % N  6.73 % Br  38.39                          Found:         40.3        7.0       6.7        38.2                           ______________________________________                                    

Step B 5-[[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-pentanol

To a solution of 10 g of 4-pentanol, 200 ml of methylene chloride, 19.5 ml of triethylamine and 566 mg of 4-dimethylamino pyridine, there were added with cooling, 19.14 g of tert-butyldimethylsilyl chloride. The mixture was stirred for one hour at ambient temperature, diluted with water and the decanted organic phase was washed, dried and evaporated to dryness under vacuum. The 42 g of residue were chromatographed on silica (eluant: essence G-ethyl acetate 95-5) to obtain 23.3 g of silyloxy pentene that was dissolved in 250 ml of tetrahydrofuran. 6 ml of borane-methylsulfide complex were added at 20° C. and the mixture was stirred for 30 minutes at 20° to 25° C., then for 30 minutes at 35° C. 18 ml of sodium hydroxide and then 18 ml of oxygenated water were added at 10° C. and the mixture was stirred for 30 minutes and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with a 10% sodium thiosulfate solution, dried and concentrated to dryness under reduced pressure. The 25.85 g of the residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 8-2) to obtain 22.7 g of product which was distilled under reduced pressure (0.06 mbar) to obtain 18.7 g of the desired compound with a boiling point of 73° to 75° C. at 0.06 mbar.

Step C N-butyl-[(5-hydroxypentyl)-oxy]-N-methyl acetamide

To a solution of 8 g of the alcohol of Step B in 40 ml of tetrahydrofuran there were added 2.16 g of 50% sodium hydride in oil. The mixture was stirred for 30 minutes at ambient temperature and then a solution of 9.5 g of the brominated compound of Step A in 13 ml of tetrahydrofuran was added dropwise over 15 minutes. The mixture was stirred for 16 hours at ambient temperature and a saturated aqueous solution of ammonium chloride was added. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness under vacuum to obtain 14.8 g of intermediate N-butyl-[5-[(dimethyl-(1,1-dimethylethyl)-silyl]-oxyl]-pentyl)-oxy]-N-methyl acetamide which was dissolved in 83 ml of tetrahydrofuran and 46 ml of a 1M solution of tetrabutyl ammonium fluoride. The mixture was stirred for 2 hours at ambient temperature and then poured into water and extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure and the 13.6 g of residue were chromatographed on silica (eluant: methylene chloride-isopropanol 94-6) to obtain 7.28 of the desired compound.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         --OH                   3628 cm.sup.-1                                          C═O                1645 cm.sup.-1                                          ______________________________________                                    

Step D [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide

To a solution of 7.2 g of the product of Step c in 73 ml of methylene chloride, there were added at -10° C., 13 g of tetrabromoethane and 10.3 g of triphenylphosphine and the reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 7.49 g of the desired compound.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O                1644 cm.sup.-1                                          ______________________________________                                         Analysis: C.sub.12 H.sub.24 BrNO.sub.2 ; molecular weight                      ______________________________________                                         = 294.24                                                                       Calculated:                                                                            % C    48.98  % H  8.22 % N  4.76 % Br  27.15                          Found:         48.6        8.2       4.6        26.3                           ______________________________________                                    

EXAMPLE 43 N-butyl-[5-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide Step A N-butyl-[5-[4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

To a solution of 2.5 g of the product of Step A of the Preparation of Example 41 in 26 ml of acetone and 6.4 ml of 2N sodium hydroxide, there were added 3.75 g of [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide (obtained in the above preparation) in solution in 6 ml of acetone. The mixture was stirred for 5 hours at 50° C., cooled and poured into water. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. After washing, drying and evaporating to dryness under reduced pressure, the 6.8 g of residue were chromatographed on silica (eluant: ethyl acetate) to obtain 2.63 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O            1735 cm.sup.-1 (17-keto)                                                       1657 cm.sup.-1                                              C═C + Aromatic 1609, 1580, 1509 cm.sup.-1                                  ______________________________________                                    

Step B N-butyl-[5-[4-(3-hydroxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

Using the procedure of Step A of Example 2, 2.61 g of the product of Step A and 2.61 g of palladium hydroxide over magnesium oxide were reacted to obtain after chromatography on silica (eluant: ethyl acetate-essence G 9-9), 1.83 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3598 cm.sup.-1                                              C═O            1732 cm.sup.-1 (17-keto)                                                       1634 cm.sup.-1 (amide III)                                  Aromatic           1611, 1581, 1511 cm.sup.-1                                  ______________________________________                                    

Step C N-butyl-[5-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien -11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

Using the procedure of Step B of Preparation 1, 500 mg of the product of Step B 66 mg of sodium borohydride were reacted. The 514 mg of residue were chromatographed on silica (eluant: methylene chloride-isopropanol 95-5), then a second time (eluant: ethyl acetate) to obtain 343 mg of the desired product with a specific rotation of [α]_(D) =-31.1° (c=1% in chloroform).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3603 cm.sup.-1                                              C═O            1634 cm.sup.-1 (amide III)                                  Aromatic           1611, 1581, 1511 cm.sup.-1                                  ______________________________________                                         Analysis: C.sub.36 H.sub.51 NO.sub.5 ; molecular weight                        ______________________________________                                         = 577.81                                                                       Calculated:                                                                             % C     74.83   % H   8.89  % N   2.42                                Found:           74.8          9.0         2.3                                 ______________________________________                                    

EXAMPLE 44 N-butyl-[5[-4-(3,17β-dihydroxy-19-nor-17α-Δ¹,3,5(10) -pregnatrien-20-yn-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

To a solution of 500 mg of the product of Example 43 in 4 ml of tetrahydrofuran, there were added 6 ml of a 0.44M solution of potassium acetylide in tetrahydrofuran (prepared by bubbling acetylene through a solution of potassium tert-butylate in tetrahydrofuran) and after stirring for 30 minutes, the mixture was poured into a saturated solution of ammonium chloride. After extraction with ethyl acetate, followed by washing, drying and evaporating to dryness under reduced pressure, the 504 mg of residue were chromatographed on silica (eluant: ethyl acetate-essence G 85-15), then under pressure (eluant: methylene chloride-acetone 90-10) to obtain 264 mg of desired product with a specific rotation of [α]_(D) =-107°±2.5° (c=0.8% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3600 cm.sup.-1                                              C.tbd.CH           3304 cm.sup.-1                                              C═O            1634 cm.sup.-1                                              Aromatic           1611, 1581, 1511 cm.sup.-1                                  ______________________________________                                         Analysis: C.sub.38 H.sub.51 NO.sub.5 ; molecular weight                        ______________________________________                                         = 601.83                                                                       Calculated:                                                                             % C     74.83   % H   8.54  % N   2.32                                Found:           74.8          8.6         2.2                                 ______________________________________                                    

PREPARATION OF EXAMPLE 45 8-[4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-phenoxy]-octanoic acid Step A 3-(1,2-ethanediyl) cyclic acetal of 11β-[4-[(8-hydroxyacetyl)-oxy]-phenyl]-5α-hydroxy-Δ⁹ -estren-3,17-dione

Using the procedure of Step A of Example 43, 1.5 g of the product of Step A of the Preparation of Example 41 and 2.22 g of 8-bromo octanol were reacted to obtain after chromatography on silica (eluant: ethyl acetate-methylene chloride 6-4), 1.475 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH             3620, 3509 cm.sup.-1                                            17-keto        1733 cm.sup.-1                                                  Aromatic       1609, 1577, 1508 cm.sup.-1 of the type                                         --C.sub.6 H.sub.4 OH                                            ______________________________________                                    

Step B 11β-[4-[(8-hydroxy-octyl)-oxy]-phenyl]-Δ⁴,9 -estradien-3,17-dione

Using the procedure of Step B of Preparation 2, 1.44 g of the product of Step A were reacted to obtain after chromatography on silica (eluant: ethyl acetate-methylene chloride 1-1), 1.049 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3620 cm.sup.-1                                              17-keto            1735 cm.sup.-1                                              Dienone            1658 cm.sup.-1                                              C═C + Aromatic 1609, 1580, 1509 cm.sup.-1                                  ______________________________________                                    

Step C 8-[4-(3,17-dioxo-Δ⁴,9 -estradien-11β-yl)-phenoxy]-octanoic acid

Using the procedure of Step C of Preparation 2, 1,008 g of the product of Step B and 1.25 ml of Heilbron-Jones reagent were reacted to obtain 1.009 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Acid (according to the OH region) with                                                              1710 cm.sup.-1                                            C═O:                                                                       17-keto              1735 cm.sup.-1                                            Dienone              1658 cm.sup.-1                                            C═C + aromatic   1609, 1580, 1509 cm.sup.-1                                ______________________________________                                    

EXAMPLE 45 8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl-N-isopropyl octanamide Step A 8-[4-(3,17β-dioxo-Δ⁴,9 -estradien-11β-yl)-phenoxy]-N-methyl-N-isopropyl octanamide

Using the procedure of Step A of Example 3, 1 g of the product of the Preparation and 1.03 ml of N-isopropyl methylamine were reacted to obtain after chromatography on silica (eluant: ethyl acetate-methylene chloride 60-40), 722 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Amide III            1621 cm.sup.-1                                            17-keto              1735 cm.sup.-1                                            Dienone              1658 cm.sup.-1                                            C═C + Aromatic   1580, 1509 cm.sup.-1                                      ______________________________________                                    

Step B 8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl-N-isopropyl octanamide a) Aromatization

Using the procedure of Step A of Example 2, 695 mg of the product of Step A and 0.7 ml of acetic anhydride and 0.35 ml of acetyl bromide were reacted to obtain 815 mg of the crude intermediate 3-acetoxy compound.

b) Saponification

Using the procedure of Step A of Example 2, 677 mg of crude 3-hydroxy-17-keto product were obtained.

c) Reduction of the Ketone at Position 17

Using the procedure of Example 28, 767 mg of lithium tritertbutoxy alumino hydride were reacted to obtain after chromato graphy on silica (eluant: ethyl acetate-methylene chloride 6-4), then successively, under pressure, methanol-water (85-15), (75-25) and finally twice with ethyl acetate-methylene chloride (6-4), 211 mg of the desired product with a specific rotation of [α]_(D) =-45°±2° (c=0.7% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3603 cm.sup.-1                                              C═O            1619 cm.sup.-1 (amide III)                                  Aromatic           1612, 1581, 1511 cm.sup.-1                                  ______________________________________                                         Analysis: C.sub.36 H.sub.51 NO.sub.4 ; molecular weight                        ______________________________________                                         = 561.81                                                                       Calculated:                                                                             % C     76.96   % H   9.15  % N   2.49                                Found:           77.3          9.3         2.5                                 ______________________________________                                    

PREPARATION OF EXAMPLE 46 8-bromo-N-butyl-N-methyl-octanamide

Using the procedure of Step A of Example 3, 5 g of 8-bromo octanoic acid and 13 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 95-5), 6.14 g of the expected product.

IR Spectrum: (CHCl₃) C═0 (tertiary amide type): 1627 cm⁻¹

EXAMPLE 46 N-butyl-8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl octanamide Step A 8-[4-(3,17β-dioxo-Δ⁴,9 -estradien-11β-yl)-phenoxy]-N-butyl-N-methyl octanamide

Using the procedure of Step A of Example 43, 725 mg of the product of the Preparation of Example 43 and 0.2 ml of 8-bromo-N-butyl-N-methyl octanamide obtained in the above preparation were reacted to obtain after chromatography on silica (eluant: essence G-ethyl acetate 4-6), 540 mg of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         17-keto          1735 cm.sup.-1                                                3-keto           1657 cm.sup.-1                                                Amide III        1628 cm.sup.-1                                                Aromatic bands   1580, 1509 cm.sup.-1 of the type                                               --O--C.sub.6 H.sub.5                                          ______________________________________                                    

Step B 8-[4-(3-hydroxy-17-oxo-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-butyl-N-methyl octanamide

Using the procedure of Step A of Example 2, 470 mg of the product of Step A and 260 mg of palladium hydroxide over magnesium oxide were reacted to obtain after chromatography on silica (eluant: ethyl acetate-essence G 1-1), 360 mg of the desired compound.

    ______________________________________                                         IR SPectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                   3596 cm.sup.-1                                            C═O              1732 cm.sup.-1                                            Amide III            1623 cm.sup.-1                                            Aromatic bands       1581, 1511 cm.sup.-1                                      ______________________________________                                    

Step C N-butyl-8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien -11β-yl)-phenoxy]-N-methyl octanamide

Using the procedure of Step B of Preparation 1, 360 mg of the product of Step B and 72 mg of sodium borohydride were reacted to obtain the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3602 cm.sup.-1                                              C═O            1623 cm.sup.-1 (amide III)                                  Aromatic           1581, 1511 cm.sup.-1                                        ______________________________________                                    

EXAMPLE 47 N-butyl-8-[4-(3,17β-dihydroxy-19-nor-17α-Δ¹,3,5(10) -pregnatrien-20-yn-11β-yl)-phenoxy]-N-methyl octanamide Step A N-butyl-8-[4-(17β-hydroxy-3-oxo-19-nor-17α-Δ⁴,9 -pregnadien-20-yl-11β-yl)-phenoxy]-N-methyl octanamide

Using the procedure of Step A of Example 43, 1.975 g of 17β-hydroxy-11β-(4-hydroxyphenyl)-19-nor-17-Δ⁴,9 -pregnadien-20-yn-3-one (prepared according to French Patent No. 2,522,328) and 1.9 ml of 8-bromo-N-butyl-N-methyl octanamide (Preparation A of Example 46) were reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclohexane 7-3), 2.45 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH              3598 cm.sup.-1                                                 C.tbd.CH        3305 cm.sup.-1                                                 C═O         1644 and 1628 cm.sup.-1 amide III                              C═C + Aromatic                                                                             1611, 1508 cm.sup.-1                                           ______________________________________                                    

Step B N-butyl-N-methyl-8-[4-[3-oxo-17β-(tetrahydro-2H-2-pyranyloxy]-19-nor-17α-Δ⁴,9 -pregnadien-11β-yl)-phenoxy]-octanamide

To a solution of 2.45 g of the compound of Step A in 25 ml of anhydrous tetrahydrofuran and 5 ml of dihydropyran, there were added 75 mg of p-toluene sulfonic acid and the mixture was stirred for 2 hours at ambient temperature. 1 ml of triethylamine was added and the mixture was diluted with a sodium bicarbonate solution. Extraction was effected with ethyl acetate and the organic phase was washed, dried, and evaporated to dryness under reduced pressure. The 4.3 g of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 2.61 g of the expected compound.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of OH                                                                  C.tbd.CH             3304 cm.sup.-1                                            C═O              1644, 1628 cm.sup.-1                                      C═C and Aromatic 1610, 1508 cm.sup.-1                                      ______________________________________                                    

Step C N-butyl-8-[4-(3,17β-dihydroxy-19 -nor-17α-Δ-¹,3,5(10) -pregnatrien-20-yl-11β-yl)-phenoxy]-N-methyl octanamide

Using the procedure of Example 8, 515 mg of the product of Step B and 0.5 ml of acetic anhydride and 0.25 ml of acetyl bromide were reacted and for the saponification, 1 ml of sodium hydroxide was used. After chromatography on silica (eluant: essence G-ethyl acetate 1-1), 460 mg of the desired product were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH             3599 cm.sup.-1                                                  C═CH       3304 cm.sup.-1                                                  C═O        1623 cm.sup.-1 amide III                                        Aromatic       1611, 1581, 1511, 1502 cm.sup.-1 (ep)                           ______________________________________                                         Analysis: C.sub.39 H.sub.53 NO.sub.4                                           ______________________________________                                         Calculated:                                                                             % C     78.09   % H   8.90  % N   2.33                                Found:           78.0          8.9         2.1                                 ______________________________________                                    

PREPARATION OF EXAMPLE 48 9-bromo-N-butyl-N-methyl-7-nonynamide Step A 6-bromo-N-butyl-N-methyl hexanamide

Using the procedure of Step A of Example 3, 4.88 g of 6-bromohexanoic acid and 4.36 ml of N-methylbutylamine were reacted to obtain 7.0 g of the expected product which was used as is for the following step.

Step B N-butyl-9-hydroxy-N-methyl-7-nonynamide

A solution of 1.77 ml of propargyl alcohol, 30 ml of tetrahydrofuran and 7.5 ml of hexamethyl phosphotriamide cooled to -60° C. was admixed with 37.5 ml of a 1.6M solution of butyllithium in hexane and after stirring for 45 minutes at -30° C., 7 g of the product of Step A in solution in 7 ml of tetrahydrofuran were added. The mixture was stirred for 16 hours at ambient temperature and then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 2N hydrochloric acid and with a saturated solution of sodium bicarbonate, dried and evaporated to dryness. The 5.78 g of residue were chromatographed on silica (eluant: methylene chloride-ethyl acetate 70-30, then methylene chloride-isopropanol 95-5) to obtain 1.65 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                3611 cm.sup.-1                                               C═O           1627 cm.sup.-1 amide                                         ______________________________________                                    

Step C 9-bromo-N-butyl-N-methyl-7-nonynamide

To a solution of 1.65 g of the product of Step B in 16.5 ml of methylene chloride cooled to -5° C. there were added 2.85 g of carbon tetrabromide and 2.25 g of triphenylphosphine. The reaction solution was stirred for 30 minutes at 0° C. and chromatogaphed on silica (eluant: methylene chloride-ethyl acetate 90-10) to obtain 1.82 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O           1628 cm.sup.-1 amide                                         C═C           2230 cm.sup.-1                                               ______________________________________                                    

EXAMPLE 48 N-butyl-9-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl-7-nonynamide Step A N-butyl-9-[4-(3,17-dioxo-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl-7-nonynamide

Using the procedure of Step A of Example 43, 816 mg of the compound of Preparation of Example 43 and 1.25 g of 9-bromo-N-butyl-N-methyl-7-nonynamide (above preparation) were reacted to obtain 2.2 g of crude product to which was added 270 mg of a previous lot. The mixture was chromatographed on silica (eluant: ethyl acetate-essence G 75-25) to obtain 1.126 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C.tbd.C            2220 cm.sup.-1                                              C═O            1735 cm.sup.-1 (17-keto)                                                       1657 cm.sup.-1 (3-keto)                                     Amide III          1628 cm.sup.-1                                              C═C + Aromatic 1610, 1582, 1508 cm.sup.-1                                  ______________________________________                                    

Step B N-butyl-9-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl-7-nonynamide

Using the procedure of Steps B and C of Example 3, 1.1 g of the product of Step A and 1.1 ml of acetic anhydride and 0.55 ml of acetyl bromide were reacted to obtain the 3-acetoxy. 2.8 ml of 2N sodium hydroxide were used for the saponification at the 3-position and 142 mg of sodium borohydride were used for the reduction of the 17-keto. After successive chromatography on silica (eluant: ethyl acetate-essence G 70-30), micro-bondapack C₁₈ (eluant: methanol-water 80-20), then again on silica (eluant: ethyl acetate-essence G 70-30), 540 mg of desired product with a specific rotation of [α]_(D) =-67°±2° (c=0.83% in chloroform) were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3606 cm.sup.-1                                              C═C            2220 cm.sup.-1                                              C═O            1620 cm.sup.-1                                              Aromatic           1582, 1510 cm.sup.-1                                        Analysis: C.sub.38 H.sub.51 NO.sub.4 ; molecular weight = 585.83               Calculated:                                                                               % C 77.91 % H 8.77   % N 2.39                                       Found:     78.0      9.0        2.3                                            ______________________________________                                    

EXAMPLE 49 N-butyl-9-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl nonanamide

A solution of 212 mg of the product of Example 48 and 42 mg of Wilkinson catalyst in solution in 2 ml of toluene and 2 ml of ethanol were hydrogenated under 1900 mbars for one hour and after filtering, the filtrate was evaporated under reduced pressure. The 265 mg of residue were chromatographed on silica (eluant: ethyl acetate-essence G 70-30) to obtain 168 mg of the desired compound with a specific rotation of [α]_(D) =-32° (c=0.49% in CHCl₃).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3603 cm.sup.-1                                              C═O            1624 cm.sup.-1                                              Aromatic           1581, 1511 cm.sup.-1                                        Analysis: C.sub.38 H.sub.55 NO.sub.4                                           Calculated:                                                                               % C 77.37 % H 9.4    % N 2.38                                       Found:     77.4      9.6        2.4                                            ______________________________________                                    

PREPARATION OF EXAMPLE 50 17β-acetyloxy-11β-(10-hydroxy-decyl)-Δ⁴,9 -estradien-3-one Step A 3-(1,2-ethanediyl cyclic acetal) of 11β-[11-[[(1,1-dimethylethyl)-sily]-oxy]-decyl]-5α-hydroxy-.DELTA.⁹ -estrene-3,17-dione

Using the procedure of Step A of Preparation 5, 19.5 g of the epoxide of EP No. 0,057,115 (Example 7) and 113.5 ml of a 0.59M solution of 10-(dimethyl-tert-butylsilyloxy)-decyl magnesium compound were reacted to obtain 43.78 g of crude product to which was added 11.3 g of a previous preparation. The mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 7-3) to obtain 23.15 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH              3616 cm.sup.-1 (at position 17)                                                3508 cm.sup.-1 (at position 5)                                 C═O         1732 cm.sup.-1 (17-keto)                                       ______________________________________                                    

Step B (1,2-ethanediyl cyclic acetal) of 5α, 17β-dihydroxy-11β-[[10-[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-decyl]-Δ⁹ -estren-3-one

Using the procedure of Step B of Preparation 5, 23.57 g of the product of Step A and 1.447 g of sodium borohydride were reacted to obtain 22.342 g of the desired product. 103 mg of the product were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 96.8 mg of pure product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                   3612, 3510 cm.sup.-1                                      t-butyldimethylsilyloxy                                                                             1255, 836 cm.sup.-1                                       ______________________________________                                    

Step C (1,2-ethanediyl cyclic acetal) of 17β-acetyloxy-11β-[[10-[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-decyl]-5α-hydroxy-Δ⁹ -estrene-3-one

Using the procedure of Step C of Preparation 5, 22.225 g of the product of Step B and 44.5 ml of pyridine and 22.25 ml of acetic anhydride were reacted to obtain 23.74 g of the expected product.

Step D 17β-acetyloxy-11β-(10-hydroxy-decyl)-Δ⁴,9 -estradien-3-one

Using the procedure of Step D of Preparation 5, 23.74 g of the product of Step C and 100 ml of 2N hydrochloric acid were reacted and chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 15.238 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3616 cm.sup.-1                                              Dienone            1654, 1600 cm.sup.-1                                        ______________________________________                                    

EXAMPLE 50 17β-hydroxy-N-methyl-N-isopropyl-3-oxo-Δ⁴,9 -estradien-11β-decanamide Step A 17β-acetoxy-3-oxo-Δ⁴,9 -estradien-11β-decanoic acid

Using the procedure of Step E of Preparation 5, 942 mg of 17β-acetoxy-3-oxo-Δ⁴,9 -estradien-11β-decanol (obtained in the above preparation) and 1.1 ml of Heilbron-Jones reagent were reacted to obtain 964 mg of the expected product which was used as is for the next step.

Step B 17β-acetoxy-N-methyl-N-isopropyl-3-oxo-Δ⁴,9 -estradien-11β-decanamide

Using the procedure of Step A of Example 3, 940 mg of the product of Step A and 0.41 ml of methylisopropylamine were reacted to obtain after chromatography on silica (eluant: essence G-ethyl acetate 1-1), 705 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                OAC           1728 cm.sup.-1                                                   Dienone       1653 cm.sup.-1                                                   Amide III     1622 cm.sup.-1                                            ______________________________________                                    

Step C 17β-hydroxy-N-methyl-N-isopropyl-3-oxo-Δ⁴,9 -estradien-11β-decanamide

Using the procedure of Step B of Example 1, 194 mg of the compound of Step B and 0.3 ml of 2N sodium hydroxide were reacted to obtain after chromatography of silica (eluant: ethyl acetate), 165 mg of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                             OH            3613 cm.sup.-1                                                   Dienone       1644 cm.sup.-1                                                   Amide III     1621 cm.sup.-1                                            Analysis: C.sub.32 H.sub.51 NO.sub.3 ; molecular weight = 497.77               Calculated:                                                                               % C 77.21 % H 10.32   % N 2.81                                      Found:     77.1      10.3        2.8                                           ______________________________________                                    

EXAMPLE 51 3,17β-dihydroxy-N-methyl-N-isopropl-Δ¹,3,5(10) -estratrien-11β-decanamide

Using the procedure of Example 2, 0.5 g of the compound of Example 50 and 0.5 ml of acetic anhydride and 0.25 ml of acetyl bromide were reacted during aromatization and 1.6 ml of 2N sodium hydroxide were used for the saponification. After chromatography on silica (eluant: ethyl acetate-essence G 7-3) 357 mg of the expected product were obtained. After crystallization from ethyl acetate, 318 mg of the desired product melting at 150° C. were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                  3605 cm.sup.-1                                             C═O (amide)     1617 cm.sup.-1                                             Aromatic            1583, 1498 cm.sup.-1                                       Analysis: C.sub.32 H.sub.51 NO.sub.3 ; molecular weight = 497.77               Calculated:                                                                               % C 77.21 % H 10.32   % N 2.81                                      Found:     77.4      10.5        2.9                                           ______________________________________                                    

EXAMPLE 52 10-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-decyl methyl isopropyl carbamate Step A 10-(17β-acetoxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-decyl methyl isopropyl carbamate

To a solution of 470 mg of 17β-acetoxy-3-oxo-Δ⁴,9 -estradien-11β-decanol (obtained in the Preparation of Example 50) in 4 ml of toluene and 122 mg of dimethylamino pyridine at 0° C., 118 mg of triphosgene were added and the mixture was stirred for 30 minutes at ambient temperature. 312 ml of methylisopropylamine were added and the mixture was stirred for 30 minutes at ambient temperature and then poured into 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness. The 642 mg of residue were chromatographed on silica (eluant: essence G-ethyl acetate 6-4) to obtain 545 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O (OAC)        1728 cm.sup.-1                                            C═O (amide)      1672 cm.sup.-1                                            C═O (dienone)    1657 cm.sup.-1                                            C═C conjugated   1601 cm.sup.-1                                            ______________________________________                                    

Step B 10-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-decyl methyl-isopropyl-carbamate

Using the procedure of Step B of Example 1, 293 mg of the product of Step A and 1 ml of 2N sodium hydroxide were reacted to obtain after chromatography on silica (eluant: essence G-ethyl acetate 1-1), 244 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      Carbamate          1672 cm.sup.-1                                              Dienone            1657, 1600 cm.sup.-1                                        OH                 3615 cm.sup.-1                                              Analysis: C.sub.33 H.sub.53 NO.sub.4 ; molecular weight = 527.79               Calculated:                                                                               % C 75.10 % H 10.12   % N 2.65                                      Found:     74.9      10.1        2.7                                           ______________________________________                                    

EXAMPLE 53 10-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-decyl methyl isopropyl carbamate Step A 10-(3,17β-diacetoxy-Δ¹,3,5(10) -estratrien-11β-yl)-decyl methyl isopropyl carbamate

Using the procedure of Step A of Example 8, 230 mg of the compound of Step A of Example 52 and 230 ml of acetic anhydride and 115 ml of acetyl bromide were reacted to obtain 234 mg of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O      1730 cm.sup.-1 (OAC at position 17)                                            1750 cm.sup.-1 (OAC at position 3)                                             1680 cm.sup.-1 (carbamate)                                        ______________________________________                                    

Step B 10-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-decyl methyl isopropyl carbamate

Using the procedure of Step B of Example 8, 260 mg of the product of Step A were reacted to obtain after chromatography on silica (eluant: essence G-ethyl acetate 6-4), 245 mg of the desired product.

    ______________________________________                                         Analysis: C.sub.33 H.sub.53 NO.sub.4 ; molecular weight = 527.79               Calculated:                                                                             % C     75.10   % H   10.12 % N   2.65                                Found:           75.6          10.5        2.6                                 IR Spectrum: (CHCl.sub.3)                                                      OH                3606 cm.sup.-1                                                ##STR48##        1672 cm.sup.-1                                               Aromatic          1619, 1610, 1583, 1498 cm.sup.-1                             ______________________________________                                    

EXAMPLE 54 3,17β-dihydroxy-17α-methyl-N-methyl-isopropyl-Δ¹,3,5(10) -estratrien-11β-undecanamide Step A 3-hydroxy-N-methyl-N-isopropyl-17-oxo-Δ¹,3,5(10) -estratrien-11β-undecanamide

One agitated under reflux for 30 minutes 1 g of the product of Step A of Example 15 with 200 ml of methanol as well as 2.2 g of palladium hydroxide on magnesium compound were refluxed with stirring for 30 minutes and was then filtered. Evaporation of the solvents under reduced pressure yielded 985 mg of product which was chromatographed on silica (eluant: acetonitrile) to obtain 543 mg of the desired product with a specific rotation of [α]_(D) =+121°±3° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3598 cm.sup.-1                                                C═O          1732 cm.sup.-1 (17-keto)                                                       1619 cm.sup.-1                                                Aromatic         1582, 1499 cm.sup.-3                                          ______________________________________                                    

Step B 3,17β-dihydroxy-N-methyl-N-isopropyl-19-nor-17α-Δ¹,3,5(10) -pregnatrien-20-yn-11β-undecanamide

To a solution of 0.5 g of the product of Step A in 10 ml of anhydrous tetrahydrofuran at 20° C., 13.7 ml of 0.6M ethyl magnesium bromide were added and the mixture was stirred for 2 hours then poured into an ammonium chloride solution. The mixture was extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. The 466 mg of residue were chromatographed on silica (eluant: methylene chloride-acetone 9-1) to obtain 225 mg of the expected product melting at 148° C. and with a specific rotation of [α]_(D) =+83°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3640 cm.sup.-1                                                 ##STR49##       1617 cm.sup.-1 (amide III)                                    Aromatic         1582, 1498 cm.sup.-1                                          Analysis: C.sub.32 H.sub.55 NO.sub.3 ; molecular weight = 525.82               Calculated:                                                                             % C     77.66   % H   10.54 % N   2.66                                Found:           77.9          10.8        2.5                                 ______________________________________                                    

EXAMPLE 55 3,17β-dihydroxy-N-methyl-N-isopropyl-19-nor-17α-Δ¹,3,5(10) -pregnatrien-20-yn-11β-undecanamide

Using the procedure of Step C of Example 21, 0.954 g of the product of Step A of Example 54 and 1.470 g of lithium acetylide-ethylene diamine complex were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 9-1), 284 mg of the desired product with a specific rotation of [α]_(D) =+43.5°±3° (c=0.2% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3600 cm.sup.-1                                                C.tbd.C          3305 cm.sup.-1                                                Aromatic         1582, 1499 cm.sup.-1                                          Analysis:                                                                      C.sub.35 H.sub.53 NO.sub.3 ; molecular weight = 535.82                         Calculated:                                                                               % C    78.46   % H  9.97  % N  2.61                                 Found:            78.5         9.9        2.4                                  ______________________________________                                    

EXAMPLE 56 3-hydroxy-11β-(11-(methyl-isopropyl-amino)-11-oxo-undecyl)-Δ.sup.1,3,5(10) -estratrien-17β-yl propanoate Step A 11β-N-methyl-N-isopropyl-Δ¹,3,5(10) -estratrien-unde canamide 3,17β-dipropanoate

To a solution of 0.511 g of the product of Step B of Example 16 in 5.1 ml of pyridine, 0.3 ml of propionyl chloride were added and the mixture was stirred for 105 minutes and 0.1 ml of propionyl chloride was added and the mixtures was stirred for 90 minutes, then poured into 30 g of water and ice. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and distilled to dryness under reduced pressure to obtain 0.848 g of the product that was chromatographed on silica (eluant: cyclohexane-ethyl acetate 6-4).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of OH                                                                   ##STR50##        1750 cm.sup.-1                                                                 1725 cm.sup.-1                                                                 1624 cm.sup.-1 (amide III)                                   Aromatic          1496 cm.sup.-1                                               ______________________________________                                    

Step B 3-hydroxy-11β-(11-(methyl-isopropyl amino)-11-oxo-undecyl)-Δ¹,3,5(10) -estratrien-17β-yl propanoate

To a solution of 0.34 g of the product of Step A in 4 ml of methanol, there were added 55 mg of potassium bicarbonate in solution in 0.4 ml of above. The mixture was stirred for 22 hours at ambient temperature and water was added. The mixture was extracted with methylene chloride and the organic phase was washed, dried and evaporated to dryness under reduced pressure. The 0.304 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 6-4) to obtain 0.285 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3600 cm.sup.-1                                                Carbamate        1720 cm.sup.-1                                                C═O (amide)  1617 cm.sup.-1                                                Aromatic         1582, 1498 cm.sup.-1                                          Analysis:                                                                      C.sub.36 H.sub.57 NO.sub.4 ; molecular weight = 567.86                         Calculated:                                                                               % C    76.14   % H  10.12 % N  2.47                                 Found:            76.4         10.3       2.3                                  ______________________________________                                    

EXAMPLE 57 N,N-bis-isopropyl-17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-undecanamide Step A N,N-bis-isopropyl-17β-acetyloxy-3-oxo-Δ⁴,9 -estradien-11β-undecanamide

Using the procedure of Step A of Example 3, 1.44 g of 17β-acetyloxy-3-oxo-11-Δ⁴,9 -estradien-undecanoic acid of Step E of Preparation 5 and 2.1 ml of diisopropylamine were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 0.533 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OAC              1728 cm.sup.-1                                                Dienone          1654 cm.sup.-1                                                ______________________________________                                    

Step B N,N-bis-isopropyl-17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-undecanamide

Using the procedure of Step B of Example 1, 248 mg of the compound of Step A were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 91 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3618 cm.sup.-1                                                C═O          1552, 1442 cm.sup.-1                                          Amide III        1620 cm.sup.-1                                                Analysis:                                                                      C.sub.35 H.sub.57 NO.sub.3 ; molecular weight = 539.85                         Calculated:                                                                               % C    77.87   % H  10.64 % N  2.59                                 Found:            77.6         10.7       2.5                                  ______________________________________                                    

EXAMPLE 58 N,N-bis-isopropyl-3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-undecanamide

Using the procedure of Example 8, 0.952 g of the product of Step A of Example 57 were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 302 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3607 cm.sup.-1                                                C═O          1617 cm.sup.-1 (amide III)                                    Aromatic         1582, 1498 cm.sup.-1                                          ______________________________________                                    

EXAMPLE 59 3,17β-dihydroxy-α-N-dimethyl-N-isopropyl-Δ¹,3,5(10) -estratrien-11β-undecanamide Step A 3,17β-bis-(tetrahydropyranyloxy)-N-methyl-N-isopropyl-Δ¹,3,5(10) -estratrien-11β-undecanamide

For one hour, a mixture of 1.045 g of the product of Step B of Example 16, 50 ml of ether, 3.75 ml of dihydropyran and 30 mg of p-toluene sulfonic acid was stirred and was then poured into 100 ml of a saturated solution of sodium bicarbonate and was extracted with ether. The ether extract was evaporated to dryness under reduced pressure to obtain 2.216 g of resin which was chromatographed on silica (eluant: methylene chloride-acetone 95-5) to obtain 1.38 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         Absence of OH                                                                  C═O          1621 cm.sup.-1 (amide III)                                    Aromatic         1573, 1497 cm.sup.-1                                          ______________________________________                                    

Step B 3,17β-dihydroxy-α-N-dimethyl-N-isopropyl-Δ¹,3,5(10) -estratrien-11β-undecanamide

Using the procedure of Step B of Example 39, 435 mg of the product of Step A were reacted to obtain 430 mg of product, the pyranyls of which were hydrolyzed by stirring in a mixture of 4 ml of ethanol and 4 ml of 2N hydrochloric acid. After concentration to half volume under reduced pressure, and extraction with methylene chloride, and chromatography on silica (eluant: methylene chloride-methanol 95-5), 0.178 g of the desired product having a specific rotation of [α]_(D) =+90°±2° (c=0.15% in ethanol) were obtained.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3605 cm.sup.-1                                                C═O          1615 cm.sup.-1 (amide III)                                    Aromatic         1582, 1498 cm.sup.-1                                          ______________________________________                                    

EXAMPLE 60 3,17β-dihydroxy-α,α-dimethyl-N-methyl-N-isopropyl-Δ.sup.1,3,5(10) -estratrien-11β-undecanamide

Using the procedure of Step C of Example 39, 210 mg of product of Step A of Example 59 were reacted to obtain after chromatography on silica (eluant:methylene chloride-acetone 96-5), 103 mg of the desired product with a specific rotation of [α]_(D) =+72°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHC.sub.3)                                                       OH               3604 cm.sup.-1                                                C═O          1600 cm.sup.-1                                                Aromatic         1580, 1498 cm.sup.-1                                          Analysis:                                                                      C.sub.35 H.sub.57 NO.sub.3                                                     Calculated:                                                                               % C    77.87   % H  10.64 % N  2.59                                 Found:            77.9         10.8       2.5                                  ______________________________________                                    

EXAMPLE 61 1-(11-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-1-oxo-undecyl)-4-methyl-piperazine Step A 1-(11-(17β-acetyloxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-1-oxo-undecyl)-4-methyl piperazine

Using the procedure of Step A of Example 3, 3.886 g of the acid of Step E of Preparation 5 and 4.33 ml of N-methyl piperazine were reacted to obtain after chromatography on silica (eluant: ethyl acetate-methanol 95-5, then 90-10), 3.14 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O          1730 cm.sup.-1 (OAC)                                          Dienone +        1646 cm.sup.-1                                                N--C═O                                                                     ______________________________________                                    

Step B 1-(11-(17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-yl)-1-oxo-undecyl)-4-methyl piperazine

Using the procedure of Step B of Example 1, 1.398 g of the product of Step A were reacted to obtain after chromatography on silica (eluant: methylene chloride-methanol 95-5), 1.012 g of the expected product with a specific rotation of [α]_(D) =-36°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3615 cm.sup.-1                                                C═O          1642 cm.sup.-1                                                Analysis:                                                                      C.sub.34 H.sub.54 N.sub.2 O.sub.3 ; molecular weight = 538.82                  Calculated:                                                                               % C    75.78   % H  10.10 % N  5.20                                 Found:            75.9         10.1       5.1                                  ______________________________________                                    

EXAMPLE 62 4-[11-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-1-oxo-undecyl]-4-methyl piperazine

Using the procedure of Example 2, 1.619 g of the product of Step A of Example 61 were reacted to obtain after two successive chromatographies on silica (eluant: methylene chloride-methanol 95-5), 466 mg of the desired product with a specific rotation of [α]_(D) =+70.5°±2.5° (c=0.5% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3610 cm.sup.-1                                                Amide III        1622 cm.sup.-1                                                Aromatic         1582, 1498 cm.sup.-1                                          Analysis:                                                                      C.sub.34 H.sub.54 N.sub.2 O.sub.3 ; molecular weight = 538.82                  Calculated:                                                                               % C    75.78   % H  10.10 % N  5.20                                 Found:            76.0         10.0       5.1                                  ______________________________________                                    

EXAMPLE 63 N-(2-chloro-2-methylpropyl)-17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-undecanamide Step A N-(2-chloro-2-methylpropyl)-17β-acetyloxy-3-oxo-Δ⁴,9 -estradien-11β-undecanamide

Using the procedure of Step A of Example 3, 2.35 g of the compound of Step E of Preparation 5 and 2.5 ml of 2,2-dimethylaziridine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 92.5-7.5) 0.08 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         ═C--NH       3445 cm.sup.-1                                                OAC              1728 cm.sup.-1                                                Dienone +        1657 cm.sup.-1                                                Amide II                                                                       Amide II         1517 cm.sup.-1                                                ______________________________________                                    

Step B N-(2-chloro-2-methylpropyl)-17β-hydroxy-3-oxo-Δ⁴,9 -estradien-11β-undecanamide

Using the procedure of Step B of Example 1, 720 mg of the product of Step A were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 420 mg of the desired product with a specific rotation of [α]_(D) =-38°±1° (c=0.7% in ethanol).

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3610 cm.sup.-1                                                ═C--NH       3444 cm.sup.-1                                                C═O          1657 cm.sup.-1                                                                 (amide II + dienone)                                          Amide II         1517 cm.sup.-1                                                ______________________________________                                    

EXAMPLE 64 N-(2-chloro-2-methylpropyl)-3,17beta-dihydroxyestra-1,3,5(10)-trien-11beta-undecanamide Stage A N-(2-chloro-2-methylpropyl)-3,17beta-diacetyloxyestra-¹,3,5(10) -trien-11beta-undecanamide

One operates as in Stage A of Example 8 starting with 970 mg of the product obtained in Example 63 using 1 cm³ of acetyl bromide and 2 cm³ of acetic anhydride. After chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), one obtains 650 mg of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         NH               3445 cm.sup.-1                                                OAc              1748, 1727 cm.sup.-1                                           ##STR51##       1668 cm.sup.-1                                                amide II         1516 cm.sup.-1                                                aromatic         1614, 1580, 1494 cm.sup.-1                                    ______________________________________                                    

Stage B N-(2-chloro-2-methylpropyl)-3,17beta-dihydroxyestra-1,3,5(10)-trien-11beta-undecanamide.

One operates as in Stage B of Example 8 starting with 640 mg of the product obtained in Stage A above. After chromatography on silica (eluant:cyclohexane-ethyl acetate 6-4) one obtains 512 mg of expected product. [alpha]_(D) =+83°±3° (c=0.5% ethanol)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                  3604 cm.sup.-1                                             CNH                 3441 cm.sup.-1                                              ##STR52##          1665 cm.sup.-1                                             amide II                                                                       +                   1619, 1610, 1521, 1499 cm.sup.-1                           aromatic                                                                       ______________________________________                                    

EXAMPLE 65 3,17beta-dihydroxy-N-methoxy-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide Stage A 17beta-acetyloxy-N-methoxy-N-methyl-3-oxo-estra-4,9-dien-11beta-undecanamid

One operates as in Stage A of Example 3 starting with 1.93 g of the product obtained as in Stage E of preparation 5 using 1.3 cm³ of N-O-dimethylhydroxylamine. After chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), one obtains 1.867 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OAC                       1728 cm.sup.-1                                       conjugated ketone                                                              +                         1653 cm.sup.-1                                       amide III                                                                      C═C                   1601 cm.sup.-1                                       ______________________________________                                    

Stage B 3,17bis-(acetyloxy)-N-methoxy-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide

One operates as in Stage A of Example 8 starting with 935 mg of the product obtained above using 0.75 cm³ of acetyl bromide and 1.5 cm³ of acetic anhydride. After chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), one obtains 898 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         acetate          1727, 1746 cm.sup.-1                                          amide III        1647 cm.sup.-1                                                aromatic         1583, 1494 cm.sup.-1                                          ______________________________________                                    

Stage C 3,17beta-dihydroxy-N-methoxy-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide

One operates as in Stage B of Example 8 starting with 850 mg of product obtained in Stage B above. After chromatography on silica (eluant: cyclohexane-ethyl acetate 6-4), one obtains 630 mg of the desired product. [alpha]_(D) =+92°±2° (c=1% ethanol)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3604 cm.sup.-1                                              amide III          1643 cm.sup.-1                                              aromatic           1583, 1498 cm.sup.-1                                        Analysis: C.sub.31 H.sub.49 NO.sub.4 : 499.74                                  Calculated:                                                                             C %     74.51   H %    9.88 N %   2.80                                Found:           74.4          10.1        2.7                                 ______________________________________                                    

EXAMPLE 66 17beta-hydroxy-N-methoxy-N-methyl-3-oxo-estra-4,9-dien-11beta-undecanamide

One operates as in Stage B of Example 1 starting with 770 mg of the product obtained in Stage A of Example 65. After chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1) one obtains 690 mg of the desired product. [alpha]_(D) =-38°±1° (c=0.65% ethanol)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                    3614 cm.sup.-1                                           dienone + amide III   1652 cm.sup.-1                                           C═ C              1601 cm.sup.-1                                           Analysis: C.sub.31 H.sub.49 NO.sub.4 : 499.74                                  Calculated:                                                                             C %     74.51   H %   9.88  N %   2.80                                Found:           74.5          9.8         2.6                                 ______________________________________                                    

PREPARATION OF EXAMPLE 67 17beta-acetyloxy-11beta-(11-hydroxy-indecyl)-estra-4,9-dien-3-one

One operates as in preparation 5 (Stages B, C, D) starting with 5.8 g of product obtained in Stage A of preparation 8. After chromatography on silica (eluant: cyclohexane-ethyl acetate 6-4), one obtains 2.847 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                3624 cm.sup.-1                                               C═ O          1730 cm.sup.-1 (OAC)                                         dienone           1654, 1601 cm.sup.-1                                         ______________________________________                                    

EXAMPLE 67 17beta-hydroxy-N-methyl-N-(1-methylethyl)-3-oxo-estra-4,9-dien-11beta-dodecanamide Stage A 17beta-acetyloxy-N-methyl-N-(1-methylethyl)-3-oxo-estra-4,9-dien-11beta-dodecanamide

One operates as in Stage A of Example 1 starting with 2.847 g of product obtained in the above preparation using 4.8 cm³ of Heilbron-Jones reagent. One obtains 2.787 g of intermediate acid. One carries out the amidification starting with 2 g of this crude acid using 1.6 cm³ of N-methyl isopropylamine. After chromatography on silica (eluant: methylene chloride-acetone 95-5), one obtains 1.8 g of desired product.

    ______________________________________                                         IR Spectrum: (CHCL.sub.3)                                                      ______________________________________                                                               1728 cm.sup.-1 (OAC)                                     C═ O                                                                                            1653 cm.sup.-1 (dienone)                                  C═ O             1621 cm.sup.-1 (amide III)                                ______________________________________                                    

Stage B 17beta-hydroxy-N-methyl-N-(1-methylethyl)-3-oxo-estra-4,9-dien-11beta-dodecanamide

One operates as in Stage B of Example 1 starting with 545 mg of the product obtained above. After chromatography on silica (eluant: toluene-triethylamine 95-5), one obtains 420 mg of expected product. [alpha]_(D) =-25°±2° (c=0.5% ethanol)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                   3613 cm.sup.-1                                                                  1643 cm.sup.-1 (dienone)                                 C═ O                                                                                            1621 cm.sup.-1 (amide III)                                Analysis: C.sub.34 H.sub.55 NO.sub.3 : 525.82                                  Calculated:                                                                             C %     77.46   H %   10.54 N %   2.66                                Found:           77.4          10.6        2.5                                 ______________________________________                                    

EXAMPLE 68 3,17beta-dihydroxy-N-methyl-N-(1-methylethyl)-estra-1,3,5(10)-trien-11beta-dodecanamide

One operates as in Example 2 starting with 1.276 g of the product obtained in Stage A of Example 67. After chromatography on silica (eluant: toluene-triethylamine 9-1), one obtains 735 mg of desired product. [alpha]_(D) =+86.5°±2.5° (c=0.6% ethanol)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH               3605 cm.sup.-1                                                C═ O         1617 cm.sup.-1 (amide III)                                    aromatic         1582, 1498 cm.sup.-1                                          ______________________________________                                    

EXAMPLE 69 (E) 12-(3,17beta-dihydroxy-N-methyl-N-(1-methylethyl)-estra-1,3,5(10)-trien-11beta-yl)-2-dodecanamide Stage A 10-(17beta-acetoxy-3-oxo-estra-4,9-dien-11beta-yl)-decanal

To a solution of 0.18 cm³ of oxalyl chloride and 5 cm³ of methylene chloride, cooled to -70° C., one adds, drop by drop, a solution of 0.29 cm³ of dimethylformamide in 5 cm³ of methylene chloride. One agitates for 15 minutes at -60° to -70° C. and adds 650 mg of the product obtained in the preparation of Example 50, in solution in 5 cm³ of methylene chloride. One agitates for 30 minutes at -60° C. and adds 2 cm³ of triethylamine. One brings the mixture to ambient temperature, dilutes with water, extracts with methylene chloride, washes with water, dries and evaporates to dryness under reduced pressure. One chromatographs on silica (eluant: cyclohexane-ethyl acetate 7-3) and obtains 580 mg of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═ O aldehyde + acetate                                                                          1723 cm.sup.-1                                           dienone               1655, 1601 cm.sup.-1                                     ______________________________________                                    

Stage B (E) 12-(17beta-acetoxy-N-methyl-N-(1-methylethyl)-3-oxo-estra-4,9-dien-11beta-yl)-2-dodecanamide Preparation of the Phosphorane

To a solution of 1 cm³ of N-methyl-N-isopropyl bromacetamide in 20 cm³ of ether one adds 2 g of triphenylphosphine. One agitates the mixture for 3 hours, separates the precipitate by decantation, triturates it in ether, separates it again by decantation, and takes it up in water. One washes the solution obtained with ether and alkalizes it with 2N soda, one extracts with ether, dries and evaporates to dryness under reduced pressure. One obtains 980 mg of expected phosphorane. From the ethereal liquors one recovers an additional 1.190 g of phosphorane.

Condensation

To a solution of the aldehyde obtained in Stage A above in 5 cm³ of tetrahydrofuran one adds a solution of 653 mg of phosphorane, obtained previously, in 6 cm³ of tetrahydrofuran. One leaves the mixture for 43 hours at ambient temperature, evaporates the solvent and chromatographs the residue on silica (eluant: cyclohexane-ethyl acetate 1-1). One obtains 580 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OAC                   1728 cm.sup.-1                                           dienone               1655 cm.sup.-1                                           conjugated amide      1600 cm.sup.-1                                           ______________________________________                                    

Stage C (E) 12-(3,17beta-dihydroxy-N-methyl-N-(1-methylethyl)-estra-1,3,5(10)-trien-11beta-yl)-2-dodecanamide

One operates as in Example 8 starting with 580 mg of the compound obtained in Stage B. After chromatography on silica (eluant: ethyl acetate-cyclohexane 1-1), one obtains 430 mg of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                   3604 cm.sup.-1                                            conjugated amide III 1655, 1597 cm.sup.-1                                      aromatic bands       1498 cm.sup.-1                                            Analysis: C.sub.34 H.sub.53 NO.sub.3 : 523.81                                  Calculated:                                                                             C %     77.96   H %   10.19 N %   2.67                                Found:           77.8          10.3        2.4                                 ______________________________________                                    

PREPARATION OF EXAMPLE 70 3-(1,2-ethanediyl cyclic acetal) of 5alpha-hydroxy-11beta-(12-hydroxy-dodecyl)-estr-9-en-3,17-dione

One agitates, for 3 hours, 4.2 g of the compound obtained in Stage A of preparation 8 with 29 cm³ of a 1M solution of tetrabutylammonium fluoride. One adds 200 cm³ of a sodium bicarbonate solution, agitates for 30 minutes, then extracts with methylene chloride. One evaporates to dryness and chromatographs the residue (6.27 g) on silica (eluant: methylene chloride-acetone 9-1). One obtains 2.43 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                OH           3602 cm.sup.-1                                                    C═ O     1733 cm.sup.-1                                             ______________________________________                                    

EXAMPLE 70 3,17beta-dihydroxy-N-methyl-N-(1-methylethyl)-estra-1,3,5(10)-trien-11beta-tridecanamide Stage A (5alpha, 11beta)-3-(1,2-ethanediyl cyclic acetal) of 5-hydroxy-11-[12-[phenylmethyl sulphonyloxy]-dodecyl]-estr-9-en-3,17-dione

One operates as in Stage A of Example 40 starting with 3.65 g of the compound obtained in the above preparation using 5 g of paratoluenesulphonyl chloride. After chromatography on silica (eluant: methylene chloride-acetone 9-1) one obtains 3.54 g of expected product, used just as it is for the following stage.

Stage B (5alpha,11beta)-3-(1,2-ethanediyl cyclic acetal) of 5-hydroxy-11-[12-[iodo]-dodecyl]-estr-9-en-3,17-dione

One operates as in Stage B of Example 40 starting with 3.5 of the product obtained in Stage A using 1.17 g of sodium iodide. One obtains 4.199 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                OH           3506 cm.sup.-1                                                    C═ O     1733 cm.sup.-1                                             ______________________________________                                    

Stage C 13-[(5alpha,11beta)-3-(1,2-ethanediyl cyclic acetal) of 5-hydroxy-11beta-yl]-tridecane nitrile

One operates as in Stage C of Example 40 starting with 4.19 g of the compound obtained in Stage B above using 1.1 g of potassium cyanide. After chromatography on silica (eluant: cyclohexane-ethyl acetate 6-4), one obtains 2.423 g of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                OH           3504 cm.sup.-1                                                    C.tbd. N     2388 cm.sup.-1                                                    C═ O     1733 cm.sup.-1                                             ______________________________________                                    

Stage D 13-[11beta-yl-estra-4,9-dien-3,17-dione]-tridecane nitrile

One operates as in Stage B of preparation 2 starting with 2.4 g of the product obtained in Stage C above. One obtains 2.11 g of the desired compound.

Stage E 13-[3-acetyloxy-17-oxo-1,3,5(10)-trien-11beta-yl]-tridecanediyl

One operates as in Stage B of Example 3 starting with 2.04 g of the product obtained in the previous Stage D. After chromatography on silica (eluant: cyclohexane-ethyl acetate 5-5), one obtains 2 fractions, A=1.1 g and B=0.817 g, of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3) on fraction A                                        ______________________________________                                         C.tbd. N         2240 cm.sup.-1                                                C═ O         1735 cm.sup.-1                                                                 1758 cm.sup.-1 (ep)                                           aromatic         1607, 1581, 1493 cm.sup.-1                                    ______________________________________                                    

Stage F 3-isobutylcarbonyloxy-N-butyl-N-methyl-17-oxo-estra-1,3,5(10)-trien-11beta-tridecanamide

One operates as in Stage E of Example 40 starting with 0.817 g of the product B obtained in the previous stage using 0.54 cm³ of N-methylisobutylamine. After chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), one obtains 603 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═ O         1753, 1735, 1621 cm.sup.-1                                    ______________________________________                                    

Stage G 3-isobutylcarbonyloxy-17beta-hydroxy-N-butyl-N-methyl-1,3,5(10)-trien-11beta tridecanamide

One operates as in a) of Stage F of Example 40 starting with 573 mg of the compound obtained in Stage F above using 406 mg of tritertbutoxy alumino hydride. After chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), one obtaines 325 mg of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                C═ O     1756 cm.sup.-1                                                    amide III    1621 cm.sup.-1                                                    aromatic     1494 cm.sup.-1                                             ______________________________________                                    

Stage H 3,17beta-dihydroxy-N-methyl-N-(1-methylethyl)-estra-1,3,5(10)-trien-11beta-tridecanamide

One operates as in Stage B of Example 2 starting with 283 mg of the product obtained in Stage G above. After chromatography on silica (eluant: cyclohexane-ethyl acetate 4-6), one obtains 215 mg of the expected product. [alpha]_(D) =-17°±1° (c=1% ethanol)

    ______________________________________                                         Analysis: C.sub.35 H.sub.57 NO.sub.3 : 539.85                                  ______________________________________                                         Calculated:                                                                             C %     79.38   H %   9.54  N %   2.50                                Found:           79.3          9.7         2.5                                 ______________________________________                                    

PREPARATION OF EXAMPLE 71 [(8-bromooctyl)-oxy]-dimethyl-(1,1-dimethylethyl)-silane

One operates as in preparation 13 starting with 3.97 g of 8-bromooctanol, 19 cm³ of dimethylformamide, 1.55 g of imidazole and 3.32 g of dimethyl tertbutyl chlorosilane. After chromatography on silica (eluant: cyclohexane-toluene 8-2), one obtains 5.4 g of the expected product.

PREPARATION B OF EXAMPLE 71 bromo-N-methyl-N-(1-methyl-ethyl-acetamide

To a solution of 10 cm³ of acetyl bromide in 150 cm³ of ether, cooled to -20° C., one adds a solution of 26 cm³ of methylisopropylamine in 100 cm³ of ether. One leaves the mixture to return to 20° C. and agitates it for 30 minutes at 20° C. One dilutes with water, decants, extracts with ether, dries and separates by distillation. One obtains 13 g of expected product. B.p.=71°/72° under 1 mmHg.

PREPARATION C OF EXAMPLE 71 11beta-(8-hydroxyethyl)-estra-4,9-dien-3,17-dione Stage A 3-(1,2-ethanediyl) cyclic acetal of 11beta-[8-(dimethylethyl) (1,1-dimethylethyl)-silyloxy]-octyl-5alpha-hydroxy-estr-9-en-3,17-dione

One operates as in Stage A of preparation 1 starting with 3.96 g of 3-(1,2-ethanediyl cyclic acetal) of 5alpha, 10alpha-epoxy-estr-9,11-en-3,17-dione obtained according to EP 0057115 (Ex. 7) using 5.4 g of [(8-bromooctyl)-oxy]-dimethyl-(1,1-dimethylethyl)-silane (preparation A of Example 71), 1 g of magnesium turnings and 0.4 g of copper chloride. After chromatography on Lichrosorb Rp18 (eluant: methanol-water 9-1), one obtains 3.85 g of the expected compound used just as it is for the following stage.

Stage B 11beta-(8-hydroxyoctyl)-estra-4,9-dien-3,17-dione

One operates as in Stage A of preparation 6 starting with 1.77 g of the product obtained above. After chromatography on silica (eluant: methylene chloride-ethyl acetate 1-1), one obtains 1.08 g of the desired compound.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH             3624 cm.sup.-1                                                  C═O        1735 cm.sup.-1 (17-keto)                                                       1656, 1602 cm.sup.-1 (dienone)                                  ______________________________________                                    

EXAMPLE 71 [[8-(3,17beta-dihydroxy-estra-1,3,5(10)-trien-11beta-yl)-octyl]-oxy]-N-methyl-N-(1-methylethyl)-acetamide Stage A [[8-(3,17-dioxo-estra-4,9-dien-11beta-yl)-octyl]-oxy]-N-methyl-N-(1-methylethyl)-acetamide

To a solution of 570 mg of the compound obtained in the above preparation in 10 cm³ of tetrahydrofuran one adds 1.4 cm³ of bromo-N-methyl-N-(1-methylethyl)-acetamide (obtained in preparation B of Example 71) and 285 mg of sodium iodide, then 140 mg of 50% sodium hydride in oil. One agitates for one hour, pours the mixture into an N hydrochloric acid solution at 0° C. and extracts with methylene chloride. One evaporates to dryness and chromatographs the residue (2 g) on silica (eluant: ethyl acetate-ether 8-2). One obtains 350 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                                17-keto      1736 cm.sup.-1                                                    3-keto       1655 cm.sup.-1                                                    amide III    1628 cm.sup.-1                                                    C═C      1603 cm.sup.-1                                             ______________________________________                                    

Stage B [[8-(3,17beta-dihydroxy-estra-1,3,5(10)-trien-11beta-yl)-octyl]-oxy]-N-methyl-N-(1-methylethyl) acetamide

One operates as in Stages B and C of Example 3 starting with 850 mg of the product obtained in Stage A above. After chromatography on silica (eluant: ethyl acetate-hexane 75-25), one obtains 442 mg of product that one recrystallizes from ethyl acetate. One collects in this way 402 mg of desired product. M.p.=126° C.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3605 cm.sup.-1                                              C═O            1626 cm.sup.-1                                              aromatic           1583, 1498 cm.sup.-1                                        Analysis: C.sub.32 H.sub.51 NO.sub.4 : 513.77                                  Calculated:                                                                              C% 74.81   H% 10.0    N% 2.72                                        Found:    74.5       9.8        2.5                                            ______________________________________                                    

PREPARATION OF EXAMPLE 72 Stage A (1,2-ethanediyl cyclic acetal) of 5alpha, 17betadihydroxy-11beta-[11-[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-undecyl-17alpha-pregna-9-en-20-yne

One operates as in Stage C of Example 21 starting with 4 g of the product obtained in Stage A of preparation 5 using 80 cm³ of ethylenediamine and 5.97 g of lithium acetylide-ethylenediamine complex. After chromatography on silica (eluant: methylene chloride-acetone 95-5), one obtains 2.024 g of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH in position 5 and 17                                                                             3600, 3500 cm.sup.-1                                      C.tbd.C              3305 cm.sup.-1                                            OSi band              836 cm.sup.-1                                            ______________________________________                                    

Stage B 17beta-hydroxy-11beta-(11-hydroxyundecyl)-17alpha-pregna-4,9-dien-20-yn-3-one

One operates as in Stage A of preparation 6 starting with 1.05 g of product obtained in Stage A above. After chromatography on silica (eluant: methylene chloride-acetone 9-1), one obtains 0.712 g of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         OH                 3608 cm.sup.-1                                              C.tbd.CH           3304 cm.sup.-1                                              dienone            1652, 1598 cm.sup.-1                                        ______________________________________                                    

EXAMPLE 72 17beta-hydroxy-N-methyl-N-(1-methylethyl)-3-oxo-17alpha-pregna-4,9-dien-20-yn-11beta-undecanamide

One operates as in Stage A of Example 1 starting with 1.3 g of the product obtained in Stage B of the above preparation using 2.5 cm³ of Heilbron-Jones reagent, 3.11 g of barium carbonate, then 0.9 cm³ of isopropylmethylamine. After chromatography on silica (eluant: methylene chloride-acetone 9-1), one obtains 0.336 g of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                3600 cm.sup.-1                                               C.tbd.CH          3305 cm.sup.-1                                               C═O           1651, 1621 cm.sup.-1                                         Analysis: C.sub.35 H.sub.53 NO.sub.3 : 535.82                                  Calculated:                                                                              C% 78.46   H% 9.97    N% 2.61                                        Found:    78.5       9.9        2.4                                            ______________________________________                                    

EXAMPLE 73 N-butyl-17beta-hydroxy-3-methoxy-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide

To a solution of 194 mg of the product obtained in Example 13 in 3 cm³ of acetone one adds 0.2 cm³ of 2N soda. One agitates for 10 minutes at ambient temperature, then one adds 0.5 cm³ of an acetone solution of dimethyl sulphate prepared with 0.3 cm³ of dimethyl sulphate and enough acetone for 10 cm³. One agitates for 10 minutes at ambient temperature and adds 0.5 cm³ of dimethyl sulphate solution. After 20 minutes, one adds 0.2 cm³ of 2N soda then 1 cm³ of dimethyl sulphate solution. After 20 minutes, one adds another 0.2 cm³ of 2N soda then 1 cm³ of dimethyl sulphate solution. One agitates again for 30 minutes, dilutes with an ammonium chloride solution and extracts with ethyl acetate. One evaporates to dryness and chromatographs the residue (220 mg) on silica (eluant: cyclohexane-ethyl acetate 1-1) and one obtains 190 mg of desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3612 cm.sup.-1                                              C═O            1626 cm.sup.-1                                              aromatic           1574, 1500 cm.sup.-1                                        Analysis: C.sub.35 H.sub.57 NO.sub.3 : 539.85                                  Calculated:                                                                              C% 77.87   H% 10.64   N% 2.59                                        Found:    77.7       10.8       2.5                                            ______________________________________                                    

EXAMPLE 74 N-butyl-4-(17beta-hydroxy-3-methoxy-estra-1,3,5(10)-trien-11beta-yl)-N-methyl benzene octanamide

To a solution of 862 mg of the product obtained in Example 8 in 8.6 cm³ of hexamethylphosphotriamide one adds 1.54 cm³ of N soda, then drop by drop 218 mg of methyl iodide. One agitates for one hour at ambient temperature, one adds 1.5 cm³ of N soda, dilutes with water, extracts with ethyl acetate, washes, dries and brings to dryness under reduced pressure. One collects 1.017 g of product that one chromatographs on silica (eluant: toluene-triethylamine 9-1) and obtains 592 mg of desired product. [alpha]_(D) =-38.5°±2.5° (c=0.5% ethanol)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3610 cm.sup.-1                                              C═O            1626 cm.sup.-1                                              aromatic           1570, 1501 cm.sup.-1                                        Analysis: C.sub.38 H.sub.55 NO.sub.3 : 573.87                                  Calculated:                                                                              C% 79.53   H% 9.66    N% 2.43                                        Found:    79.3       9.9        2.4                                            ______________________________________                                    

PREPARATION OF EXAMPLE 75 N-heptafluorobutyl-N-methylamine hydrochloride

One cools to 0° C. 100 cm³ of anhydrous ether, 100 cm³ of anhydrous tetrahydrofuran, then bubbles through methylamine for 10 minutes. Over half an hour, one introduces 44.98 g of heptafluorobutyric anhydride, continuing to gently bubble the methylamine through it. One agitates the mixture for 2 hours, leaving it to return to ambient temperature. One distils to a small volume under reduced pressure, takes up in 200 cm³ of anhydrous tetrahydrofuran and slowly introduces 30 cm³ of diborane-dimethyl sulphide complex. One refluxes the mixture for 16 hours, then cools to it ambient temperature and slowly introduces 200 cm³ of methanol. Next one bubbles through gaseous hydrochloric acid for 15 minutes. One refluxes for one hour then distils the solvents under reduced pressure. One takes up the residue in 200 cm³ of methanol. Again one bubbles through gaseous hydrochloric acid for 10 minutes then refluxes for 2 hours. One distils the solvent, agitates for 10 minutes in 100 cm³ of ice-cooled 6N hydrochloric acid. One separates, washes with 2N hydrochloric acid, dries and obtains 22.699 g of expected product. The hydrochloride obtained above is purified by crystallization from 140 cm³ of ethanol. One then adds 140 cm³ of ether, agitates for half an hour, separates, washes with ether and dries under reduced pressure. One obtains 21.7 g of desired product (sublimating at about 200° C.).

    ______________________________________                                         Analysis: C.sub.5 H.sub.6 F.sub.7 N, HCl: 249.56                               ______________________________________                                         Calculated:                                                                            C% 24.06 H% 2.83 Cl% 14.20                                                                            F% 53.29                                                                              N% 5.61                                  Found:  24.0     2.814.4       52.3-52.1                                                                             5.6                                      ______________________________________                                    

EXAMPLE 75 3,17beta-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide Stage A 3,17-dioxo-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-estra-4,9-dien-11beta-undecanamide

One operates as in Stage A of Example 3 starting with 500 mg of the compound obtained in Stage B of preparation 6 using 0.370 cm³ of N-methylmorpholine, 0.173 cm³ of isobutyl chloroformate and 412 mg of heptafluorobutylmethylamine hydrochloride (preparation of Example 75). After chromatography on silica (eluant:essence G-ethyl acetate 6-4, pure ethyl acetate, then ethyl acetate with 1% acetic acid) one obtains 180 mg of the desired product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      ______________________________________                                         C═O      1736 cm.sup.1 (17-keto)                                                        1657 cm.sup.-1 (dienone + amide III)                              C═C      1602 cm.sup.-1                                                    ______________________________________                                    

Stage B 3-acetoxy-17-oxo-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide

One operates as in Stage B of Example 3 starting with 345 mg of the product obtained in Stage A above using 0.4 cm³ of acetic anhydride and 0.2 cm³ of acetyl bromide. One obtains 323 mg of expected product.

Stage C 3,17beta-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-estra-1,3,5(10)-trien-11beta-undecanamide

One operates as in Stage C of Example 3 starting with 323 mg of the product obtained above using 20 mg of boron and sodium hydride and 0.3 cm³ of 2N soda. After chromatography on silica (eluant:essence G-ethyl acetate 1-1), one obtains 230 mg of the expected product.

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH               3604 cm.sup.-1                                                C═O          1655 cm.sup.-1                                                aromatic         1610, 1584, 1498 cm.sup.-1                                    Analysis: C.sub.34 H.sub.48 F.sub.7 NO.sub.3 : 651.76                          Calculated:                                                                             C% 62.66  H% 7.42   N% 2.15 F% 20.4                                   Found:   62.7      7.6       2.0     20.04                                     ______________________________________                                    

EXAMPLE 76 N-butyl-(5-(4-(3,17beta-dihydroxy-19-nor-17alpha-pregna-1,3,5(10)-trien-20-yn-11beta-yl)-phenoxy)-pentylthio)-N-methyl acetamide

One operates as in Example 43 starting with 11beta-4-(hydroxyphenyl)-estra-4,9-dien-3,17-dione and (5-bromopentyl)-thio-N-butyl-N-methyl acetamide, to obtain N-butyl(5-(4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-11beta-yl)-phenoxy)-pentylthio)-N-methyl acetamide. The addition of acetylene in the presence of potassium tertbutylate leads to the expected product. [alpha]_(D) =-98.5° (c=1% CHCl₃)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH                 3599 cm.sup.-1                                              ethynyl            3305 cm.sup.-1                                               ##STR53##         1628 cm.sup.-1                                              aromatic           1581, 1512 cm.sup.-1                                        Ultra violet: (EtOH)                                                                   max 281 nm epsilon = 4000                                                      max 287 nm epsilon = 3800                                                      (EtOH + NaOH N/10)                                                             max 280 nm epsilon = 3300                                                      max 287 nm epsilon = 3500                                                      max 300 nm epsilon = 3200                                              ______________________________________                                    

EXAMPLE 77 N-butyl-(5-(4-(3,17beta-dihydroxy-estra-1,3,5(10)-trien-11beta-yl)-phenoxy)-pentylthio)-N-methyl acetamide

One reduces the N-butyl-(5-(4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-11beta-yl)-phenoxy)-pentylthio)-N-methyl acetamide obtained in Example 76 using sodium borohydride in methanol. In this way one obtains the expected product. [alpha]_(D) =-32.5° (c=0.1% CHCl₃)

    ______________________________________                                         IR Spectrum: (CHCl.sub.3)                                                      OH             3603 cm.sup.-1 + associated OH                                   ##STR54##     1627 cm.sup.-1                                                  aromatic       1581, 1511 cm.sup.-1                                            Ultra violet (EtOH)                                                                    max 281 nm epsilon = 3800                                                      max 287 nm epsilon = 3700                                                      (EtOH + NaOH N/10)                                                             max 280 nm epsilon = 3100                                                      max 287 nm epsilon = 3200                                                      max 300 nm epsilon = 2700                                              ______________________________________                                    

Pharmaceutical Compositions

One prepared tablets corresponding to the following formula:

    ______________________________________                                         Product of Example 21     50 mg                                                Excipient (talc, starch, magnesium stearate)                                                            120 mg                                                q.s. for a tablet completed at                                                 ______________________________________                                    

Pharmaceutical Compositions

Compressed tablets were prepared containing 50 mg of the product of Example 21 and sufficient excipient of talc, starch, magnesium stearate for a tablet weighing 120 mg.

PHARMACOLOGICAL DATA A-Activity on Hormonal Receptors Mineralocorticoid Receptor of the Rats' Kidney

Male Sprague-Dawley EOPS rats weighing 140 to 160 g were subjected to supraenalectomy 4 to 8 days earlier and were sacrificed and their kidneys were perfused in situ with 50 ml of a 10 mM Tris, 0.25M saccharose, HCl buffer pH 7.4. The kidneys were then removed, decapsulated and homogenized at 0° C. with the aid of a Potter teflon-glass (1 g of tissue for 3 ml of buffer). The homogenate was centrifuged for 10 minutes at 800 mg and 0° C. and then to eliminate the fixation of the tritiated aldosterone upon the glucocorticoid receptor, 11β-,17β-dihydroxy-21-methyl-Δ¹,4,6 -pregnatrien-20-yn-3-one which was fixed uniquely upon the glucocorticoid receptor was added to the supernatant at a final concentration of 10⁻⁶ M. This supernatant was ultracentrifuged at 105,000 g for 60 minutes at 0° C. and aliquotes of the supernatant thus obtained were incubated at 0° C. with a constant concentration (T) of tritiated aldosterone in the presence of increasing concentrations (0-2500.0⁻⁹ M) of the cold aldosterone or the cold product to be studied. After an incubation time (t), the concentration of bound tritiated aldosterone (B) was measured by the adsorption on dextran carbon technique.

Androgen Receptor of Rat's Prostate

Male Sprague Dawley EPOS rats weighing 160 to 200 g were castrated and 24 hours after the castration, the animals were killed. Their prostates were removed, weighed and homogenized at 0° C. using a Potter teflon-glass in a TS buffered solution (Tris 10 mM, saccharose 0.25M, HCl pH 7.4) (1 g of tissue for 5 ml of TS). The homogenate was ultracentrifuged (105,000 g for 60 minutes) at 0° C. and aliquots of the supernatant were incubated at 0° C. for an incubation time E with a constant concentration (T) of tritiated testosterone in the presence of increasing concentrations (0-1000.10⁻⁹ M) either of cold testosterone or of the product to be tested. The concentration of bound tritiated testosterone (B) was then measured in each incubate by the adsorption on dextran carbon technique.

Progestogen Receptor of Rabbit's Uterus

Impuberal rabbits weighing about 1 kg received a cutaneous application of 25 μg of estradiol and 5 days after this treatment, the animals were killed. The uteri were removed, weighed and homogenized at 0° C. using a Potter teflon-glass in a TS buffered solution (Tris 10 mM, Saccharose 0.25M, HCl pH 7.4) (1 g of tissue for 50 ml of TS). The homogenate was then ultracentrifuged (150,000 g×90 minutes) at 0° C. and aliquots of the supernatant were incubated at 0° C. for a time t, with a constant concentration (T) of the tritiated product R (17,21-dimethyl-19-nor-Δ⁴,9 -pregnandiene-3,20-dione in the presence of increasing concentrations (0-2500.10⁻⁹ M) either of cold R or of cold progesterone, or of the cold product to be tested. The concentration (B) of bound tritiated R was subsequently measured in each incubate by the technique of adsorption on dextran charcoal.

Glucocorticoid Receptor of Rat Thymus

Male Sprague Dawley EOPS rats weighing 160 to 200 g were subjected to suprarenalectomy and 4 to 8 days after this intervention, the animals were killed. The thymuses were removed and homogenized at 0° C. in a 10 mM Tris, 0.25M saccharose, 2 mM dithiothreitol, HCL pH 7.4 buffer, with the aid of a Potter polytetrafluoroethylene-glass (1 g of tissue for 10 ml of TS). The homogenate was subsequently ultracentrifuged (105,000 g×90 min) at 0° C. and aliquots of the supernatant were incubated at 0° C. for a time (t) with a constant concentration (T) of tritiated dexamethasone in the presence of increasing concentrations (0-2,500.10⁻⁹ M) either of cold dexamethasone, or of cold product to be tested. The concentration (B) of the bound tritiated dexamethasone was measured in each incubate by the adsorption technique on dextran carbon.

Estrogenic Receptor of Mouse Uterus

Impuberal female mice aged from 18 to 21 days were killed and their uteri were removed, then homogenized at 0° C. with the aid of a Potter teflon-glass in a TS buffered solution (10 mM Tris, 0.25M saccharose, HCL pH 7.4) (1 g of tissue for 25 ml of TS). The homogenate was ultracentrifuged (105,000 g×90 min) at 0° C. and aliquots of the supernatant were incubbated at 0° C. or at 25° C. for a time (t) with a constant concentration (T) of tritiated estradiol in the presence of increasing concentrations (0-1000×10⁻⁹ M) either of cold estradiol, or of the cold product to be tested. The concentration (B) of bound tritiated estradiol was measured in each incubate by the technique of adsorption on dextran carbon.

Calculation of the Relative Affinty of the Bond

The calculation of the Relative Affinity of the Bond (RAB) was identical for all the receptors. The following 2 curves were traced; the percentage of the bound tritiated hormone B/T was a function of the logarithm of the concentration of the cold reference hormone and B/T as a function of the logarithm of the concentration of the cold product tested.

One determined the straight line of the equation

    I.sub.50 =(B/Tmax+B/Tmin)/2.

B/T max=percentage of the bound tritiated hormone for an incubation of this tritiated hormone at the concentration (T).

B/T min=percentage of the bound tritiated hormone for an incubation of this tritiated hormone at the concentration (T) in the presence of a great excess of cold hormone (2500×10⁻⁹ M).

The intersections of the straight line I₅₀ and of the curves make it possible to evaluate the concentrations of the cold reference hormone (CH) and of the tested cold product (CX) which inhibit to an extent of 50% the binding of the tritiated hormone upon the receptor. The relative affinity of the bond (RAB) of the tested product is determined by the equation

    RAB=100(CH)/(CX)

The results obtained are as follows:

    __________________________________________________________________________     Incubation                                                                              Mineralo            Glucocoti-                                        period at 0° C.                                                                  corticoid                                                                            Androgen                                                                              Progestogen                                                                           coid  Oestrogen                                   Product Examples                                                                        1 H                                                                               24 H                                                                              0.5 H                                                                              25 H                                                                              2 H                                                                               24 H                                                                               4 H                                                                               24 H                                                                              2 H 5 H                                     __________________________________________________________________________      8       0.09                                                                              0.09                                                                              0   0.06                                                                              2.3                                                                               9   4.5                                                                               8  0.12                                                                               23                                      13       0.19                                                                              0.08                                                                              0   0.12                                                                              0.8                                                                               1.8 7  7  0.13                                                                               27                                      16       0  0  0   0.4                                                                               0.5                                                                               2   12 11 0.5 50                                      21       0.4                                                                               0.5                                                                               0   0  0.3                                                                               1   2  2.5                                                                               0.05                                                                               7.4                                     24       0  0  0   0.4                                                                               0  0   2  3  0.02                                                                               13                                      17       2  0.5                                                                               0.12                                                                               1.2                                                                               8  15  3  6  0.1 <0.01                                   19       0.7                                                                               0.1                                                                               11  11 6  7   5  4.5                                                                               0.3 0.8                                     22       0  0  0.8 0  12 21  7  14 <0.01                                                                              <0.01                                   35                                 0.13                                                                               12                                      37                                 0.6 28                                      43                                 4.0 3,0                                     46                                 0.3 65                                      55                                 1.2 45                                      71                                 0.6 50                                      __________________________________________________________________________

Conclusion

The products studied, particularly the products of Examples 8, 13, 16, 37, 46, 55 and 71 had a marked affinity for the estrogen receptors at the second time. The product of Example 19 had a moderate affinity for the androgen receptor and the products of Examples 17 and 22 for the pregesterone receptor. Furthermore, the majority of the products are free of uterotrophic activity.

B. Anti-Proliferative Activity of the Products of the Invention Upon the Growth of MCF-7 Mammary Tumoral Cells Description of the Test a) Cell Culture

The MCF-7 strains were kept under culture in FCS(1) medium at 37° C. under a humid atmosphere containing 5% CO₂ and the cells at subconfluence were harvested by trypsination (0.05% trypsine, 0.02% EDTA), then rinsed by gentle centrifugation. A sample of the cells in suspension was counted on Malassez cell.

b) Growth Study

The cells, resuspended in FCS medium, were seeded at a rate of 30,000 cells per pit in multi-pit plates (24 pits of 2.5 cm²) and twenty four hours after seeding (DO), the product to be tested was added to the medium in ethanolic solution (final concentration in ethanol: 0.1%), at a concentration of 10⁻¹² to 10⁻⁶ M, the control pits receiving the same concentration of ethanol. The media were renewed every 48 hours and at the end of the experiment (D6), the medium was sucked off and the cells were immediately fixed with 150 microliters of methanol to estimate the DNA. The anti-proliferative activity of the products was evaluated by their capacity to inhibit the increase of DNA.

c) Measurement of DNA

The DNA was measured by a fluorimetric method employing DABA (3,5-diaminobenzoic acid) (2): 150 microliters of DABA were added to each of the pits and the plates were then incubated for 45 minutes at 56° C., then 2 ml of 1N HCl were added. The fluorescence was measured with the aid of a fluorimeter (length of the exiting wave: 408 nm, length of the emitting wave: 501 nm). The quantity of DNA per pit was evaluated with reference to a standard scale obtained by treating a standard DNA from calf thymus under the same conditions.

Results

The concentration in nM which inhibited the growth of MCF₇ to an extent of 50% (IC₅₀) was determined in the manner indicated below:

Results

Product of Example 8: IC₅₀ =0.04 nM

Product of Example 13: IC₅₀ =0.5 nM

Product of Example 16: IC₅₀ =0.02 nM

Product of Example 21: IC₅₀ =0.02 nM

Product of Example 24: IC₅₀ =0.06 nM

Product of Example 35: IC₅₀ =0.04 nM

Product of Example 37: IC₅₀ =0.03 nM

Product of Example 43: IC₅₀ =0.002 nM

Product of Example 46: IC₅₀ =0.006 nM

Product of Example 55: IC₅₀ =0.01 nM

Product of Example 71: IC₅₀ =0.1 nM

Furthermore, the maximum inhibitor effect of the products reached about 90%.

(1) The fetal calf serum (FCS) culture medium was prepared as follows: MEM medium (minimal essential medium) to which were added:

Non-essential amino acids (GIBCO),

Peni-strepto (100 U/ml penicillin, 0.1 mg/ml streptomycin),

Fungizone 0.1%

Insulin (50 ng/ml),

Fetal calf serum containing no steroids (10% final concentration).

(2) Puzas and Goodman, Analytical Biochemistry, Vol. 86, pp. 50, 1978.

Various modifications of the products and method of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in the appended claims. 

What we claim is:
 1. Novel 19-nor-steroids of the formula ##STR55## wherein the A and B rings have a structure ##STR56## R₃ is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and acyl of an organic carboxylic acid of 1 to 7 carbon atoms, R₁₇ and R'₁₇ together form ═0 or R₁₇ is --OH or acyloxy and R'₁₇ is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms, all optionally substituted with at least one member of the group consisting of halogen, alkoxy, alkylthio, --NH₂, mono- or dialkylamino, optionally oxidized amino-alkyl, dialkylaminoalkyl, dialkylaminoalkoxy, --OH, acyloxy, free or esterified carboxy, --CN, --CF₃, phenyl, furyl, thienyl, benzyl, X is selected from the group consisting of --CH₂ --, --CH₂ O--, phenylene and phenylenoxy linked to the C ring through a carbon atom, Y is selected from the group consisting of a simple bond and saturated and unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of phenylene, --O--and optionally oxidized --S-- and optionally terminated with phenylene, Z is a simple bond or --CH₂ --O-- linked to Y by a carbon atom, R_(A) and R'_(A) being individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of aryl, alkylamino, dialkylamino, --OH, halogen and esterified carboxyl with the proviso 1) that both of R_(A) and R'_(A) are not hydrogen and 2) when Z and Y are both simple bonds, X is not --CH₂ -- or --CH₂ --O--.
 2. A compound of claim 1 wherein Z is a simple bond.
 3. A compound of claim 1 wherein R₁₇ is --OH.
 4. A compound of claim 1 wherein R₁₇ ' is hydrogen or ethynyl or propynyl.
 5. A compound of claim 1 wherein X is --CH₂ -- and Y is linear alkylene of 5 to 10 carbon atoms optionally interrupted by --O--.
 6. A compound of claim 1 wherein X is phenylene and Y is an aliphatic linear chain of 3 to 10 carbon atoms optionally interrupted by --O--.
 7. A compound of claim 1 wherein X is phenylenoxy and Y is a linear alkylene of 3 to 10 carbon atoms optionally interrupted by --O-- or --S--.
 8. A compound of claim 1 wherein R_(A) and R_(A) ' are both methyl or R_(A) is methyl and R_(A) ' is selected from the group consisting of isopropyl, dimethylaminoethyl, benzyl and heptafluorobutyl or R_(A) ' is butyl and R_(A) is hydrogen or methyl.
 9. A antiestrogenic composition comprising an antiestrogenically effective amount of at least one compound of claim 1 and an inert pharmaceutical carrier.
 10. A method of inducing hormonal activity in warm-blooded animals comprising administering to warm-blooded animals an antiestrogenically effective amount of at least one compound of claim
 1. 11. A compound of claim 1 selected from the group consisting of N-butyl-4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-N-methyl-benzene octanamide; 3,17β-dihydroxy-N-methyl-N-isopropyl-Δ¹,3,5(10) -estratrien-11β-yl-undecananide; N-butyl-N-methyl-3,17β-dihydroxy-19-nor-17α-Δ¹,3,5, (10) -pregnatrien-20-yne-11β-yl-undecanamide; N-methyl-N-isopropyl-3,17β-dihydroxy-19-nor-17α-Δ¹,3,5, (10) -pregnatrien-20-yne-11β-yl-undecanamide; [(8-l (3,17β-dihydroxy-Δ¹,3,5(10) estratrien-11β-yl)-octyl)-oxy]-N-methyl-N-isopropylacetamide; N-butyl-8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl octanamide; N-butyl-[5-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methylacetamide; 2-[[7-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl]-6-heptylyl]-oxy]-N-butyl-N-methyl acetamide; 3,17β-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-Δ.sup.1,3,5(10) -estratrien-11β-yl undecanamide and 8-[4-(3,17β-dihydroxy-Δ¹,3,5(10) -estratrien-11β-yl)-phenyl]-N-butyl-N-methyl octynamide. 